UA77532C2 - Pyridazin-3(2h)-one derivatives as phosphodiesterase 4 inhibitors - Google Patents

Abstract

New pyridazin-3(2H)-one derivatives having the chemical structure of general formula (I); are disclosed; as well as processes for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of phosphodiesterase 4. (I),

Description

Description of the invention

The present invention relates to new pyridazin-3(2H)-one derivatives, methods of their preparation, and pharmaceutical 2 compositions containing these compounds. These compounds are effective and selective inhibitors of phosphodiesterase 4 (POE4 - short: from the English rpozrpodieuziegase) and, as a result, may find use in the treatment, prevention or elimination of painful conditions, diseases, disorders and disorders, for which it is known that the patient's condition can be improved when inhibiting the activity of POE4.

Phosphodiesterases (POE5) include a superfamily of enzymes that are responsible for the hydrolysis and inactivation of 70 secondary messengers - cyclic adenosine monophosphate (cyclo-AMP) and cyclic guanosine monophosphate (cyclo-GMP). So far, eleven different families of phosphodiesterases (from POET1 to POET11) have been identified, which differ in their preferred substrate, catalytic activity, sensitivity to endogenous activators and inhibitors, as well as coding genes.

The ROE4 isozyme family exhibits high affinity for cyclic AMP, but low affinity for cyclic HMF. The increase in cyclic AMP induced by phosphodiesterase 4 (POE4) inhibition is associated with inhibition of cell activation, which is seen in a wide range of cells involved in the inflammatory process and cells of the immune system, including lymphocytes, macrophages, basophils, neutrophils, and eosinophils . In addition, inhibition of ROE4 reduces the release of the cytokine tumor necrosis factor (TNF). The biological characteristics of phosphodiesterase 4 are described in several recently published reviews (for example, in: M. 0. Noiziau, Rgod. Misieis Asii Kev. Mo).

VioI., 2001, M.69, p.249-315; 9. E. Botspevzv ei a). Ittiporpagtasoi., 2000. m. 47, p. 127-162; M. Sofia, 5. Y. ip, Rhod. Mysivys Asia Kev. Mo). Visi., 1999, m.63, p.1-38).

Taking into account the described physiological effects, ROE4 inhibitors of different chemical structures have recently been proposed to be used for the treatment or prevention of chronic and acute inflammatory diseases and other painful conditions, diseases, disorders and disorders, for which it is known that the patient's condition can be improved by inhibiting the activity ROE 4. |See, for example, patents OZ 5449686, 05 5710170, published applications MO 98/45268, MO 99/06404, MO 01/57025, MO 01/57036, UMO 01/46184, MO 97/05105, MO 96/ 40636, patents 05 5786354, 05 5773467, 5 5753666, 05 5728712, 05 5693659, OB 5679696, OB 5596013, 05 5541219, 55508300, 05 5502072 or article N. YuuKe, 9. b. Mopiapa, Ehr. Orip. Ipmevzi Ogydv, 1999, m. 8, p. 1301-13251. with

The authors of this invention have discovered that a number of new pyridazin-3(2H)-one derivatives are effective and selective co-inhibitors of ROE4 activity and thus can be used for the treatment or prevention of relevant disease states, diseases, disorders and disorders, in particular, such as asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis or increased intestinal irritability.

According to this, the present invention relates to new compounds of the formula (I) in which

B" represents: -I - a hydrogen atom; - a group selected from acyl, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl or dialkylcarbamoyl; - an alkyl group which is optionally substituted by one or more, for example, 1, 2, C or 4 substituents, 1 selected from halogen atoms and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- or cis-dialkylamino, acylamino, carbamoyl or mono- or dialkylcarbamoyl groups; - or a group of the formula -(СНо)-К, in which n means an integer from 0 to 4, and KU is:

Is - a cycloalkyl group; - an aryl group, which is optionally substituted by one or more, for example, 1, 2, C or 4 substituents selected from halogen and alkyl atoms, hydroxy, alkoxy, alkylenedioxy, alkylthio, amino, mono- or dialkylamino, nitro, acyl groups , hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- or dialkylcarbamoyl, cyano, o trifluoromethyl, difluoromethoxy or trifluoromethoxy; - or a 3-7-membered ring system that includes from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms, the specified ring system is optionally substituted by one or more, for example, 1, 2, C or 4 , by substituents selected from halogen atoms and an alkyl group, a hydroxy, alkoxy, alkylenedioxy, amino, 60 mono- or dialkylamino, nitro, cyano or trifluoromethyl group;

IN? represents a substituent selected from B / and an alkyl group, which is substituted by a hydroxycarbonyl or oxycarbonyl group; each of KZ and KE? independently represents a monocyclic or bicyclic aryl group, which is optionally substituted by one or more, for example, 1, 2, C or 4 substituents selected from: bo - halogen atoms;

- alkyl and alkylene groups, which are optionally substituted by one or more, for example, 1, 2, C or 4 substituents selected from halogen and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- or dialkylamino atoms, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl or mono- or dialkylcarbamoyl; - phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulfinyl, amino, mono- or dialkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- or dialkylcarbamoyl, ureido, M'-alkylureido, M',M '-dialkylureido, alkylsulfamido, aminosulfonyl, mono- or dialkylaminosulfonyl, cyano, difluoromethoxy or trifluoromethoxy groups;

B" represents: - a hydrogen atom; - a hydroxy, alkoxy, amino, mono- or dialkylamino group; - an alkyl group, which is optionally substituted by one or more, for example, 1, 2, C or 4, substituents selected from halogen atoms and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- or dialkylamino, acylamino, hydroxycarbonyl, hydroxycarbonyl, carbamoyl and mono- or dialkylcarbamoyl groups; - or a group of the formula -(СНо)-В2, in which n and 29 are , as above, with the proviso that in the case where VE is H and BZ and B are unsubstituted phenyl, then VE is not methyl; or pharmaceutically acceptable salts of these compounds.

Some pyridazin-3(2H)-one derivatives of a similar structure, which are not included in the scope of this invention (described in the article: 3. Rnagt. Zsi. 1991, M. 80, p. 341-348; 93. Med. Spet. 1999 , age 42, 1894-1900).

In addition, the purpose of this invention is to develop a method for obtaining the specified compounds; pharmaceutical compositions that include an effective amount of the indicated compounds; the use of compounds for the manufacture of a medicinal product intended for the treatment of such a disease, the patient's condition can be improved by inhibiting the phosphodiesterase POE4; as well as the creation of methods of treating a disease in which a patient's condition can be improved by inhibiting phosphodiesterase POE4, such methods include d) administering a compound according to the present invention to a patient in need of such treatment.

When used in the text of the application, the term "alkyl group" can mean a linear or branched group, and usually refers to a lower alkyl group. The lower alkyl group contains from 1 to 6, preferably from 1 to 4 carbon atoms. In particular, preferably, if such a group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 1-ethylpropyl, 1,2dimethylpropyl, n-hexyl or c 1-ethylbutyl.

When used in the text of the application, the term "alkylene group" or "alkylene fragment" means a divalent o alkylene fragment, which usually contains from 1 to b carbon atoms. Examples of C 4-C 6 alkylene groups M include methylene, ethylene, propylene, butylene, pentylene, and hexylene groups. In that case,

When an alkylene group or an alkylenedioxy group is present as a substituent near another group, it should be considered as a single substituent and not as a group formed by two substituents.

When using the term "alkyl chains" in the text of the application, which are in the groups of alkoxy, alkylthio, monoalkylamino, dialkylamino, alkoxycarbonyl, monoalkylcarbamoyl, dialkylcarbamoyl, alkylenedioxy, "alkylsulfinyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfamido, M'-alkylureido (and 40. M' M'-dialkylureido usually refers to linear or branched alkyl chains containing from 1 to 6 carbon atoms. When indicated in the text of the application, the acyl group or acyl fragment usually contains from 2 to 7 carbon atoms. Thus, it is usually a group of the formula -SOK, in which K means a carbon chain containing from 1 to 6 carbon atoms. Preferably, this is a group of the formula -SOK, in which K means a C.4-Cv alkyl group.

When indicated in the text of the application, the cycloalkyl group or cycloalkyl fragment usually contains from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferable -And cyclopropyl, cyclopentyl or cyclohexyl. In the case where the cycloalkyl group or cycloalkyl fragment has 2 or more substituents, the substituents may be the same or different. When using the term "cycloalkyloxy group" in the text of the application, this term usually refers to the indicated cycloalkyl group,

F3 020 attached to an oxygen atom.

When used in the text of the application, the terms "aryl group" or "aryl fragment" usually mean a C-CeO aryl group or fragment, which can be monocyclic or bicyclic, for example, phenyl or naphthyl. Where an aryl group or moiety has 2 or more substituents, these substituents may be the same or different. When used in the text of the application, the term "aryloxy group" usually means the specified aryl group attached to an oxygen atom.

GF) When the term "3-7-ene ring system" is used in the text of the application, such a system includes from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms, and usually represents a heteroaryl de or heterocyclyl group or fragment.

A heteroaryl group or heteroaryl fragment usually contains a 3-7-membered aromatic ring, 60 for example a 5- or b-membered aromatic ring, which contains at least one heteroatom selected from O, 5 and M.

Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, oxadiazolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrazolidinyl, pyrrolyl and pyrazolyl groups. Preferred groups are oxadiazolyl, oxazolyl, pyridyl, pyrrolyl, imidazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, pyrazinyl and pyrimidinyl. In the case when the heteroaryl group or fragment has 2 or more substituents, these substituents may be the same or different.

A heterocyclyl group is usually a non-aromatic, saturated or unsaturated C53-C carbocyclic group in which one or more, for example, 1, 2, 3 or 4 carbon atoms are replaced by heteroatoms selected from M, O and 5.

Saturated heterocyclic groups are preferred. Examples of suitable heterocyclyl groups include piperidinyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 3-azatetrahydrofuranyl, imidazolidinyl. and pyrrolidinyl. In the case where the heterocyclyl group has 2 or more substituents, these substituents may be the same or different.

When used in the text of the application, the term "halogen atom" usually means a chlorine, fluorine or bromine atom.

When indicating in the text of the application, some atoms, groups, fragments, chains or cycles in the general structures that characterize the invention are "optionally substituted". Such an indication means that these atoms, groups, fragments, chains or rings may be either unsubstituted or substituted with one or more, for example, 1, 2, C or 4 substituents, wherein the hydrogen atoms attached to the unsubstituted atoms, groups, fragments , chains or cycles are replaced by chemically acceptable atoms, groups, fragments, chains or cycles.

Compounds of formula (I), which contain one or more chiral centers, can be used in enantiomerically or diastereomerically pure form, or in the form of a mixture of isomers.

When used in the text of the application, the term "a pharmaceutically acceptable salt" means a salt of a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, for example, hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, hydroiodic or nitric acids, and organic acids, for example, citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, 2o benzoin, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic.

Pharmaceutically acceptable bases include alkali metal hydroxides (eg, sodium or potassium) and alkaline earth metal hydroxides (eg, calcium or magnesium), as well as organic bases, for example, alkylamines, aralkylamines, and heterocyclic amines.

Preferred compounds of formula (I) are those compounds in which B' is a hydrogen atom; linear or Ha branched C4-Su; an alkyl group, which is optionally substituted by halogen atoms and/or 1 or 2 substituents selected from hydroxy, alkoxy, amino, monoalkylamino and dialkylamino groups; or a group of the formula -"(СНо)-Б5, in which n means an integer from 0 to 4, and KZ? is an optionally substituted phenyl, cycloalkyl or 5-6-ene heterocyclic ring system that includes at least one nitrogen atom, preferably a pyridine ring system. Most preferably, B! is an unsubstituted linear or branched C 1-C; an alkyl group, or a c group of the formula -(CH0)-B, in which n means 0 or 1, and KZ is cyclopropyl, phenyl or pyridyl. co

More preferred compounds of formula (I) are those compounds in which KE? represents a hydrogen atom or a group selected from alkoxycarbonyl; carbamoyl; linear S.-S,. an alkyl group, which is optionally substituted with a hydroxy group; or a group of the formula -(CH0)y-KZ, in which n means 0, and KU is a phenyl ring, which is optionally substituted by 1 or 2 substituents selected from the group that includes halogen, alkyl, acyl, alkoxy, ich- alkylthio and alkoxycarbonyl. Most preferably, B? represents a hydrogen atom, an unsubstituted linear C 4-C 4 alkyl group or a phenyl ring, which is optionally substituted with 1 or 2 substituents selected from halogen, alkyl, acyl, alkoxy, alkylthio and alkoxycarbonyl.

Also preferred are compounds in which C is a phenyl or naphthyl group optionally substituted with 1 or 2 substituents selected from halogen, hydroxy, alkoxy, cycloalkyloxy, alkylthio, cyano, 8C nitro, acyl, hydroxycarbonyl, alkoxycarbonyl .

According to a preferred embodiment of the invention, B 7 is a substituent selected from hydrogen; hydroxy; Alkoxy; amino; monoalkylamino; dialkylamino; a linear or branched C.--Cv alkyl group, which is optionally substituted by a hydroxy, alkoxy, amino, monoalkylamino or dialkylamino group; or a group of the formula -1 -(СНо)д-25, in which n means 0, 1 or 2, and BU is a phenyl group. Most preferably, VK 7 is a substituent selected from hydrogen, methoxy, an unsubstituted linear or branched C-C alkyl group, and phenyl. According to another preferred embodiment of the invention B? is a phenyl group which 2) is optionally substituted with 1 or 2 substituents selected from halogen, hydroxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulfinyl, nitro, cyano, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, C-monoalkylcarbamoyl, dialkylcarbamoyl, ureido, M'-alkylureido, M'M'-dialkylureido and an optionally substituted linear or branched C.4-Cv alkyl group. Most preferably, KE? is a phenyl group which is optionally substituted with 1 or 2 substituents selected from halogen, alkoxy, cycloalkyloxy, alkylthio, alkylsulfinyl and nitro.

GF) Specific individual compounds include the following compounds: q 5-acetyl-2-ethyl-4-(3-fluorophenyl)amino|-6-phenylpyridazin-33(2H)-one; 5-acetyl-4-((3,5-difluorophenyl)amino|-2-ethyl-b6-phenylpyridazin-3Z(2H)-one; 5-acetyl-4-((3,5-dichlorophenyl)amino|-2 -ethyl-b6-phenylpyridazin-3Z(2H)-one; 60 5-acetyl-2-ethyl-4-((3-nitrophenyl)amino)|-b6-phenylpyridazin-3(2H)-one; 5-acetyl- 2-ethyl-4-(4-methylphenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-((2-methylphens)amino)|-6-phenylpyridazine -3(2H)-one; 5-acetyl-2-ethyl-4-((2-methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-(1 -naphthylamino)-6-phenylpyridazin-33(2H)-one;

5-acetyl-4-(4-acetylphenyl)amino|-2-ethyl-b-phenylpyridazin-3(2H)-one; 5-acetyl-4-H4-(dimethylamino)phenyl|amino)-2-ethyl-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-(2-aphthylamino)-6-phenylpyridazin-3Z(2H)-one; 5-acetyl-4-((2-chlorophenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-b6-phenyl-4-(13--'trifluoromethoxy )phenyl|amino)pyridazin-3(2H)-one; 5-acetyl-2-ethyl-β6-phenyl-4-((2-trifluoromethyl)phenyl|amino)pyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-((2,5-dimethoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-((2-fluoro-3- methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one; 70 5-acetyl-4-((2,3-dichlorophenyl)amino|-2-ethyl-b6-phenylpyridazin-3Z(2H)-one; 5 -acetyl-4-((5-chloro-2-methoxyphenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-((5-fluoro-2 -methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one; 4-(15-acetyl-2-ethyl-6-14-(methylthio)phenyl|-3-oxo-2,3-dihydropyridazin- 4-yl)iamino)benzoic acid; 5-acetyl-2-ethyl-4-((3-fluorophenyl)amino|-6-(4-(methylthio)phenyl|pyridazin-3(2H)-one; 4-( 15-acetyl-2-ethyl-6-I4-(methylthio)phenyl|-3-oxo-2,3-dihydropyridazin-4-ylamino)benzoic acid; 5-acetyl-2-ethyl-6-I4-(methylthio) phenyl|-4-(1-naphthylamino)pyridazin-3(2H)-one; 5-butyryl-2-ethyl-4-((3-fluorophenyl)amino1|-6-(14-(methylthio)phenyl|-pyridazine) -3(2H)-one; 2-ethyl-5-(2-ethylbutanoyl)-4-(3-fluorophenyl)amino)|-6-I(I4-(methylthio)phenyl|-pyridazin-3(2H)- 2-ethyl-5-(2-ethylbutanoyl)-6-I(4-(methylthio)phenyl)|-4-(naphth-1-ylamino)pyridase in-3(2H)-one; methyl ester of 4-(15-acetyl-2-ethyl-6-14-(methylsulfinyl)phenyl|-3-oxo-2,3-dihydropyridazin-4-illiamino)benzoic acid; 5-acetyl-2-ethyl-4-((3-fluorophenyl)amino|-6-(4-(methylsulfinyl)phenyl|-pyridazin-3(2H)-one; 5-acetyl-4-((3-chlorophenyl )amino|-2-ethyl-6-I(4--methylsulfinyl)phenyl|pyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-((2-methylphenyl)amino|-6- I(4-(methylsulfinyl)phenyl|pyridazin-3(2H)-one; 5-acetyl-2-ethyl-6-I4-(methylsulfinyl)phenyl|-4-(1-naphthylamino)pyridazin-3(2H)- one; i) 5-acetyl-2-ethyl-6-14-(methylsulfinyl)phenyl/|-4-(3-nitrophenyl)amino|pyridazin-3(2H)-one; 5-acetyl-2-ethyl-6 -(4-(methylsulfinyl)phenyl|-4-(2-methoxyphenyl)amino|pyridazin-3(2H)-one; 5-acetyl-2-ethyl-6-I(4-(methylsulfinyl)phenyl|-4- (3-Methoxyphenyl)amino|pyridazin-3(2H)-one; c zo 5-acetyl-6-3-(cyclopentyloxy)-4-methoxyphenyl/|-2-ethyl-4-((3-fluorophenyl)amino |pyridazin-3(2H)-one; 5-acetyl-6-3-(cyclopentyloxy)-4-methoxyphenyl|-2-ethyl-4-(1-naphthylamino)pyridazin-3(2H)-one; o 5 -acetyl-2-methyl-4-(1-naphthylamino)-6-phenylpyridazin-3(2H)-one; 5-acetyl-4-((3,5-difluorophenyl)amino|-2-methyl-b- phenylpyridazin-3(2H)-one; 5-acetyl-4-((3-chlorophenyl)amino|-2-methyl-b6-phenylpyr dazin-3(2H)-one; 1-5-acetyl-2-benzyl-4-((3,5-difluorophenyl)amino|-6-phenylpyridazin-3(2H)-one; 1-5-acetyl-2-benzyl-4-((3Z- fluorophenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-benzyl-4-(3-chlorophenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-2 -(cyclopropylmethyl)-4-(1-naphthylamino)-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-(cyclopropylmethyl)-4-((3-fluorophenyl)amino)|-6-phenylpyridazin- 3(2H)-one; « 5-acetyl-4-((3-chlorophenyl)amino|-2-(cyclopropylmethyl)-6-phenylpyridazin-3Z(2H)-one; with c 5-acetyl-4-(1 -naphthylamino)-6-phenyl-2-pyridin-4-ylmethylpyridazin-3(2H)-one; 5-acetyl-4-(3-fluorophenyl)amino|-6-phenyl-2-pyridin-4-ylmethylpyridazin- 3(2H)-one; 5-acetyl-2-ethyl-4-((3-methylphenyl)amino|-6-phenylpyridazin-3(2H)-one; 4-K5-acetyl-2-ethyl- 3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzoic acid; 2-K5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl )amino|Ibenzoic acid; -I 5-acetyl-4-((3-chlorophenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one; 5-acetyl-4-(3-bromophenyl)amino |-2-ethyl-b6-phenylpyridazin-3(2H)-one;

Ш- 5-acetyl-4-((3,4-dimethoxyphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one; c 5-acetyl-2-ethyl-4-C4-(hydroxymethyl) phenyl|amino)-6-phenylpyridazin-3(2H)-one; 5-acetyl-4-(1,1-biphenyl-4-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one; o 5-acetyl-2-ethyl-b-phenyl-4-(5,6,7 8-tetrahydronaphthalene-1-ylamino)pyridazin-3(2H)-one;

He 5-acetyl-4-II3-(cyclopentyloxy)-4-methoxyphenyl|amino)-2-ethyl-b6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-N-methyl-N-phenylamino|-b-phenylpyridazin-3Z(2H)-one; 5-acetyl-4-(1,3-benzodioxol-5-ylamino)-2-ethyl-b-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-((4-methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-4-(4-chlorophenyl)amino|-2-ethyl-6- phenylpyridazin-3(2H)-one;

F) 5-acetyl-4-(4-bromophenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one; ka 5 -acetyl-2-ethyl-b6-phenyl-4--III3--trifluoromethyl)phenyl|amino)pyridazin-3Z(2H)-one; 5-acetyl-4-((3-chloro-4-methoxyphenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one; in 5-acetyl-2-ethyl-4-((3-hydroxyphenyl )amino|-6-phenylpyridazin-3(2H)-one; 3-(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzoic acid; 5- acetyl-2-ethyl-4-((2-fluorophenyl)amino|-6-phenylpyridazin-3Z(2H)-one; 4-(5-acetyl-2-ethyl-3-oxo-6-phenyl-2-ethyl ether) ,3-dihydro-pyridazin-4-ylamino)benzoic acid; 5-acetyl-2-ethyl-4-(4-fluorophenyl)amino|-6-phenylpyridazin-3Z(2H)-one; 65 2-K5-acetyl- 2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-4-fluorobenzoic acid; 3-(5-acetyl-2-ethyl-3-oxo-6-phenyl-2 ,3-dihydropyridazin-4-yl)amino|benzonitrile;

4-K5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino)|-2-hydroxybenzoic acid; 5-acetyl-2-ethyl-4-((3-hydroxy-4-methoxyphenyl)amino|-b6-phenylpyridazin-3Z(2H)-one; 4-K5-acetyl-2-ethyl-3-oxo-6- phenyl-2,3-dihydropyridazin-4-yl)amino|Senzamide; 5-acetyl-2-ethyl-4-(13-(methylthio)phenyl|amino)-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-((3-methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-4-(3-acetylphenyl)amino|-2-ethyl-b- phenylpyridazin-3(2H)-one;

T1A-K50-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)iaminophenylacetic acid; 5-acetyl-4-I(I4-(tert-butylphenyl)amino|-2-ethyl-6-phenstridazin-3(2H)-one; 70 4-K5-acetyl-2-ethyl-3-oxo-6- phenyl-2,3-dihydropyridazin-4-yl)amino|benzenesulfonamide; 4-(A-((5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|phenyl)-4-oxobutanoic acid; 3-(5-acetyl-2 -ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-N-butylbenzenesulfonamide; 5-acetyl-2-ethyl-4-(1-oxo-2,3-dihydro-1H -inden-5-yl)amino|-6-phenylpyridazin-3(2H)-one;

M-14-(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|phenyl)acetamide; 4-(b-acetyl-6-(3-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydropyridazin-4-ylamino|benzoic acid; 5-acetyl-6-(3-chlorophenyl)-4-( 3-chlorophenyl)amino|-2-ethylpyridazin-3(2H)-one; 5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-((33-fluorophenyl)amino|pyridazin-3(2H) -one; 5-acetyl-4-(3-chlorophenyl)amino|-2-ethyl-6-(4-fluorophenyl)pyridazin-3(2H)-one; 5-acetyl-4-(3-bromophenyl)amino| -2-ethyl-6-(33-fluorophenyl)pyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-((3-fluorophenyl)amino|-6-(3-fluorophenyl)pyridazin-3 (2H)-one; 5-acetyl-4-(3-chlorophenyl)amino|-2-ethyl-6-(3-fluorophenyl)pyridazin-3(2H)-one; 5-acetyl-4-(3-chlorophenyl) )amino|-2-ethyl-6-(Z-nitrophenyl)pyridazin-3Z(2H)-one; 5-acetyl-2-ethyl-4-((Z-fluorophenyl)amino|-6-(Z-nitrophenyl) pyridazin-3Z(2H)-one; 4-(5-acetyl-2-ethyl-6-(Z-nitrophenyl)-3-oxo-2,3-dihydropyridazin-4-ylidimino)benzoic acid; 5-acetyl- 4-(3-bromophenyl)amino|-2-ethyl-6-(3-nitrophenyl)pyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-(naphthalene-1-ylamino)-6- (3-nitrophenyl)pyridazin-3(2H)-one; i) 5-butyryl-4-((3-chlorophenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one; 5- acetyl-4-(3-chlorophenyl)amino|-6-phenyl-2-propylpyridazin-3(2H)-one; 5-acetyl-2-butyl-4-((3-chlorophenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-4-(3-bromophenyl)amino|-2-butyl- b6-phenylpyridazin-3(2H)-one; 5-acetyl-4-(M-(3,5-dichlorophenyl)-M-(3-fluorophenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H) -one; o 5-acetyl-4-Ibis(3-fluorophenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one; u 5-acetyl-4-Ibis(3-chlorophenyl)amino|- 2-ethyl-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-bis(3-methylsulfanylphenyl)amino|-6-phenylpyridazin-3(2H)-one; i- 5-acetyl -4-Ibis(3-acetylphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one; ethyl-6-phenyl-2H-pyridazin-3-one; 4-(M-(5-acetyl-2-ethyl-6-(4-methylsulfinylphenyl)-3-oxo-2,3-dihydropyridazin-4-) methyl ester yl)-M-(4-(methoxycarbonyl)phenyl amino)benzoic acid; "5-acetyl-2-(cyclopropylmethyl)-4-((3,5-difluorophenyl)amino|-6-phenylpyridazine-3(2H)- 5-acetyl-4-(3-fluorophenyl)amino|-2-methyl-6-phenylpyridazin-3(2H)-one; 4-K5-acetyl-2-methyl-3-oxo-6- phenyl-2,3-dihydropyridazin-4-yl)amino|benzoic acid; 5-acetyl-4-((3,5-dichlorophenyl)amino|-2,6-diphenylpyridazin-3Z(2H)-one; 5-acetyl-4-((3-fluorophenyl)amino|-2,6-diphenylpyridazin-3Z(2H)-one; 5-acetyl-4-(1-naphthylamino)-2,6-diphenylpyridazine-3Z(2H) -one; -I 5-acetyl-4-((3,5-difluorophenyl)amino|-2,6-diphenylpyridazin-3Z(2H)-one; 5-acetyl-4-(3-chlorophenyl)amino|-2 ,6-diphenylpyridazin-3Z(2H)-one;

N-5-benzoyl-4-(3-chlorophenyl)amino|-2-ethyl-b6-methylpyridazin-3(2H)-one; c 5-(3-chlorophenyl)amino)|-1-ethyl-6b-oxo-3-phenyl-1,6-dihydropyridazine-4-carbaldehyde; 5-(3-chlorophenyl)amino)|-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid methyl ester; o 5-acetyl-2-cyclobutyl-4-((3,5-dichlorophenyl)amino)|-b-phenylpyridazin-3(2H)-one;

He 5-acetyl-4-(3-chlorophenyl)(2-hydroxyethyl)amino|-2-ethyl-b6-phenylpyridazin-3Z(2H)-one; 4-(3-chlorophenyl)amino|-5-(dimethylamino)acetyl|-2-ethyl-b6-phenylpyridazin-3(2H)-one; 4-(2-ethyl-5-(methoxyacetyl)-6-phenyl-3-oxo-2,3-dihydropyridazine-4-ylidamino)benzoic acid; 5-(3-cyanophenyl)amino)-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxamide; 5-(3-cyanophenyl)amino)-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid;

F) 3-4-acetyl-5-((3,5-difluorophenyl)amino)|-1-ethyl-6-oxo-1,6-dihydropyridazin-33-yl)/benzoic acid; ka 3-4-acetyl-5-((3,5-difluorophenyl)amino)|-1-ethyl-6-oxo-1,6-dihydropyridazin-3-ylbenzonitrile;

IM-(3--4-acetyl-5-((3,5-difluorophenyl)amino|-1-ethyl-6b-oxo-1,6-dihydropyridazin-3-iluphenyl)urea; in 5-acetyl-4- ((3-chlorophenyl)amino|-6-phenylpyridazin-3(2H)-one;

M-benzyl-5-(3-chlorophenyl)amino)-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxamide; 4-(3-chlorophenyl)amino)|-2-ethyl-5-(phenoxyacetyl)-6-phenylpyridazine-3(2H)-one.

The following compounds are of considerable interest: 5-acetyl-2-ethyl-4-(3-fluorophenyl)amino|-6-phenylpyridazin-33(2H)-one; 65 5-acetyl-4-((3,5-difluorophenyl)amino|-2-ethyl-b6-phenylpyridazin-3Z(2H)-one; 5-acetyl-2-ethyl-4-(1-naphthylamino)-6 -phenylpyridazin-3Z(2H)-one;

5-acetyl-4-((2-chlorophenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one; 4-(15-acetyl-2-ethyl-6-14-(methylthio)phenyl| -3-oxo-2,3-dihydropyridazin-4-ylamino)benzoic acid; 5-acetyl-2-ethyl-4-((2-methylphenyl)amino|-6-I(4-(methylsulfinyl)phenyl|pyridazine- 3(2H)-one; 5-acetyl-6-3-"cyclopentyloxy)-4-methoxyphenyl|-2-ethyl-4-((3-fluorophenyl)amino|pyridazin-3(2H)-one; 5-acetyl -4-((3,5-difluorophenyl)amino|-2-methyl-b-phenylpyridazin-3(2H)-one; 5-acetyl-2-(cyclopropylmethyl)-4-((3-fluorophenyl)amino)| -6-phenylpyridazin-3(2H)-one; 5-acetyl-4-((3-chlorophenyl)amino|-2-(cyclopropylmethyl)-6-phenylpyridazin-3Z(2H)-one; 4-K5-acetyl- 2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzoic acid; 70 5-acetyl-4-((3-chlorophenyl)amino|-2-ethyl-6-phenylpyridazine -3(2H)-one; 3-(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzonitrile; 4-(b-acetyl-6- (3-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydropyridazin-4-ylamino|benzoic acid; 5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-((33-fluorophenyl )amino|pyridazin-3(2H)-one; 5-acetyl-2-ethyl -4-((3-fluorophenyl)amino|-6-(3-fluorophenyl)pyridazin-3(2H)-one; 5-acetyl-4-(3-chlorophenyl)amino|-2-ethyl-6-(3-fluorophenyl)pyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-(naphthalene-1-ylamino)-6-(3-nitrophenyl)pyridazin-3(2H)-one; 5-acetyl-2-(cyclopropylmethyl)-4-((3,5-difluorophenyl)amino|-6-phenylpyridazin-3(2H)-one.

According to another embodiment, the present invention relates to methods of obtaining new pyridazine-3(2H)-one derivatives of formula (I). These compounds can be prepared by one of the methods described below.

In that case, when BC? means H, compounds of formula (I) are obtained by the interaction of the corresponding derivative 4-aminopyridazin-3(2H)-one (II) -

Ko oi Yafeni

N shk: SHY: and where KE", B" and B are as defined above, and of the corresponding boronic acid (ShA) sch in which BZ is as defined above. The reaction is carried out in the presence of a copper salt, for example, such as copper acetate, and an organic base, preferably an amine base, for example, such as triethylamine, in an inert solvent, such as dioxane, methylene chloride or tetrahydrofuran, at a temperature from -202C to temperature 39 boiling point of the solvent. -

In the event that 2? is aryl or substituted aryl, compounds of formula (I) are obtained by the interaction of the corresponding derivative 4-aminopyridazin-3(2H)-one (IM):

Ve in t.; then B -o ,» 5 s that. where B", BZ, 27 and 2? are as indicated above, and the corresponding boronic acid (IB) t -i yav), yiv c where VK? is an aryl or substituted aryl group. The reaction is carried out in the presence of a copper salt, 5o, for example, such as copper acetate, and an organic base, preferably an amine base, for example, such as o triethylamine, in an inert solvent, for example, such as dioxane, methylene chloride or tetrahydrofuran, at a temperature from -202C to the boiling point of the solvent.

Alternatively, compounds of formula (I) can be prepared by reacting the corresponding 4-nitropyridazin-3(2H)-one derivative (M): 60 ku in which EC", B" and 2 are as indicated above and the corresponding amine (M) dn b5 C, where is B? and VZ are as indicated above, using known methods, for example, the one (described in the article: 0. Sisiapi e(a). Ragtaso, 1991, M.46, p.8731).

In that case, when KK? represents alkoxy, aryloxy or mono- or dialkylamino or mono- or diarylamino, the compounds of formula (I) can be obtained by the interaction of the corresponding derivative 4-aminopyridazin-3(2H)-one (CHMII): :: what o s she min 7170 sa t where B", BZ and BZ are as above and the corresponding alcohol or amine in the presence of a condensing agent such as dicyclohexylcarbodiimide, O-7-(azabenzotriazol-1-yl)-1,1,3,- -3 tetramethyluronium 75 hexafluorophosphate (GATU) or benzotriazol-1yloxy-tris--(dimethylamino)phosphonium hexafluorophosphate (BOF) in an inert solvent such as dichloromethane, tetrahydrofuran, dioxane, M,M-dimethylformamide, and in the presence of an organic base, such as triethylamine or ethyldisopropylamine, if necessary, at a temperature from -202C to the boiling point of the solvent.

In the case where K7 is alkoxy, compounds of formula (I) can also be prepared from the corresponding derivative 4-aminopyridazin-3(2H)-one (CHMII) and a suitable alkylating agent in the presence of an inorganic base such as potassium carbonate, in an inert solvent, for example, in M,M-dimethylformamide or acetone at a temperature from -202C to the boiling point of the solvent.

Derivatives of 4-aminopyridazin-3(2H)-one of the general formula (I) can be obtained by hydrogenation of isoxazol!

ZT Ya. V shi. y so 5 ri ri 5 r5 : yuyu in which KK, K" and K? are as indicated above. Hydrogenation can be carried out using, for example, hydrogen in the presence of a catalyst according to methods known in themselves | for example, described in articles: M. Oai i-

Ria; oh oh No (egosusiez, 1991, M.32, p.1173). Alternatively, the reaction can be carried out by a transfer hydrogenation reaction using an organic hydrogen donor and a transfer agent such as ammonium formate or hydrazine using techniques known per se, for example as follows (as described in:

M. Wai Ria? oh oh No (egosusiez, 1991, M.32, p.1173).

As an alternative, in the case when BC! does not mean H, 4-aminopyridazin-3(2H)-one derivatives of the formula (I) « 0 Can be obtained by the interaction of compounds of the general formula (MIP!) - с | и- и - ши B. "» yes To "Hey Goethe -i (MIV, -I in which KE? and B? are as indicated above, with the alkylating agent of the formula (IX) and at 50 in which BC" is as defined above, and X represents a group which is removed, for example, a chlorine atom or a bromine atom, or a methanesulfonate, p-toluenesulfonate or benzenesulfonate group, using techniques known per se, for example as follows | as described in: M. Yua! Ria; ей аЙ. Eig. U. Med.

Spet., 1996, m.31, r.b651I.

Derivatives of 4-nitropyridazine-Z3(2H)-one of the formula (M) can be obtained by oxidation of isoxazolo!|3,4-4|pyridazin-7(6H)-one of the formula (MII) in which BC" . (a). Zupipeziv, 1989, p. 213).

In the case when B" does not mean H, isoxazolo!|3,4-a4|-pyridazin-7(6H)-one derivatives of the formula (MI) can be obtained by the interaction of the compound of the general formula (X)

M va in which KE? and B? are as defined above, with an alkylating agent of formula (IX) in which BK" is as defined above and X represents a leaving group, for example, such as a chlorine atom 7/5 or a bromine atom, or a methanesulfonate group, p-toluenesulfonate or benzenesulfonate, using methods that are known per se, for example as described in |M.

Oivsomegu, 1996, m.14, p.53).

Derivatives of 4-aminopyridazin-3(2H)-one of the general formula (II) as an alternative can be obtained by the interaction of the compound of the formula (CHMII):

Mona Zine is not a sch o in which B and vo are as indicated above, with an aldehyde or a ketone, using techniques known per se, for example as described in |. Sisiapi ei aiYi. II Ragtaso, 1991, M.46, p.873). The resulting substituted vinyl derivative is then reduced, using, for example, hydrogen, in the presence of a catalyst, such as palladium on carbon, in a solvent such as methanol, ethanol, or ethyl acetate, to give the corresponding 4-aminopyridazine-Z3( 2H)-one (I).

Isoxazolo!|Z,4-4|pyridazin-7(6H)-ones of the formula (MI) can be obtained from

Z-(bromomethyl)isoxazolo!|3,4-4|Ipyridazin-7(6p)-one of formula (XIX)

B Z

70 by interaction with a nucleophile, such as an alkoxide, amine or thiol using a technique that is known in itself, for example, the one described in the article (E. Mopiezapoei a. Visogd. Med. Spet. Iei., 1998, m.b., r.925). Derivatives of 4-aminopyridazin-3(2H)-one of the general formula (HMI) can be obtained by hydrogenation of isoxazolo!|3,4-4|pyridazine-3,7-dione of the formula (XX) according to 5.

I

-I Z Shk N o 20 in which B! and 2? are as above. The hydrogenation can be carried out using, for example, hydrogen in the presence of a catalyst using techniques known per se, for example as described in

Ko) articles of M. bai Ria ei a). Nefegosusiez, 1991, 32, 1173). Alternatively, the reaction can be carried out by a transfer hydrogenation reaction using an organic hydrogen donor and a transfer agent such as ammonium formate or hydrazine by techniques known per se, for example as described in |M. 22 Wai Ria? her a). Ney (egosusiez, 1991, M. 32, p. 1173).

Gee! Isoxazolo|3,4-4|Ipyridazin-3,7-diones of the formula (XX) can be obtained by the interaction of the corresponding isoxazolo!|3,4-4|pyridazin-7(6H)-one of the formula (XXI)

KO svy oy vo y y e with 65 in which B! and B? are as above and the corresponding boronic acid (Pa)

in which the VZ is as defined above. The reaction is carried out in the presence of a copper salt, for example, such as copper acetate, and an organic base, preferably an amine base, such as triethylamine, in an inert solvent, for example, such as dioxane, methylene chloride or tetrahydrofuran, at a temperature from -202C to the boiling point of the solvent .

Isoxazolo|3,4-4|Ipyridazin-7(6H)-ones of the formula (MII) and (XXI) can also be obtained, as an alternative, by the interaction of the compound of the general formula (XI) and Men z o se; c in which 27 and BZ are as defined above and B is an alkyl substituent, with a hydrazine of the general formula (XII) in which B is as defined above, using techniques known per se, for example, such as described in |b. Kep?i e(aiI., bag7. Spit. MNai. 1965, 95, 14781.

Isoxazole derivative formulas (XI) can be obtained by the interaction of 1,3-dicarbonyl compounds of the general formula SK) c with AZ; in which B" and 2" are as indicated above, and compounds of the formula (CHM) in which B is as defined above, using methods known per se, for example, such

WITH CLASS, as described in (0. Kep?i ei ai., bag7. Spit. Mai., 1965, m.95, p.14781. im-

Dicarbonyl compounds of the formula (XII) can be obtained by the interaction of methyl ketone of the formula (ХМ)

SHI

"

Su shi s in which B? is as defined above, and of the complex ester of the formula (XM) g" in which 28 means alkyl, and B? is as defined above, using techniques known per se, -1 35 for example, as described in IM. M. Roris e(ai., 5upipeviv, M. 1991, p. 195).

In the case when the specified groups K!-K? in the conditions of implementation of the methods described above are prone to chemical transformations or are incompatible with the implementation of these methods, use conventional protective groups in accordance with generally accepted practice (for example, see T. MU. Sgeepe, R. b. M. MUtsiv, "Rgoiesime Sgotsrz ip Ogdapis

Spetivhigu", ZYA Edyop, dopp UMieu 5 Zopve (1999)). Such groups can be removed to obtain compounds of formula (1) at the final stage.

GI Pharmaceutically acceptable salts of compounds according to the present invention, represented by formula (I), can be salts - addition products of an acid or salts - addition products of a base. Examples of acid addition salts include mineral acid addition salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, diphosphate, and organic acid addition salts, such as acetate, benzoate, maleate, fumarate, citrate , oxalate, ascorbate, (F. succinate, tartrate, malic acid salt, mandelic acid salt, methanesulfonate, ethanesulfonate, cobenzenesulfonate and p-toluenesulfonate. Examples of salts - base addition products include inorganic salts, for example, such as sodium, potassium, calcium, magnesium and ammonium and salts formed with organic bases, for example, such as ethylenediamine, ethanolamine, M,M-dialkyleneethanolamine, triethanolamine and salts with basic amino acids.

The compounds according to the present invention represented by the above formula (I) may include enantiomers, depending on their asymmetry, or diastereomers. The scope of this invention includes both individual isomers and mixtures of isomers. 65 Methodology for the study of the impact on ROE4

The tested compounds are suspended in DMSO, the initial concentration is 17 mM. Compounds are tested at various concentrations varying from 10µM to 1OpM in order to calculate the IC 5o value. These dilutions are carried out in 96-well plates. In some cases, tablets containing diluted compounds are frozen before testing. In these cases, the tablets are thawed at room temperature and stirred for 15 minutes.

Ten microliters of the diluted compounds are placed in a tablet for conducting the study, which has a low adhesion ("om bBipaipd"). Eighty microliters of the reaction mixture containing 500 mM Tris pH 7.5, 8.3 mM Maosi, 1.7 mM EGTA and 15 nM |IZNI-cyclo-AMP are added to each well. The reaction is initiated by adding ten microliters of a solution containing POE4. Then the tablet is incubated with stirring for 1 hour at 70 room temperature. After incubation, the reaction is stopped by adding 50 microliters of 5PA beads, and the reaction mixture is left to incubate for another 20 minutes at room temperature before measuring radioactivity using conventional equipment.

The reaction mixture is prepared by adding 10 ml of NaO to 10 ml of the buffer for the study at a dilution of 10X (500 mM Tris pH 7.5, 83 mM MoasCl, 17 mM EGTC), and 40 microliters of IZNI-cyclo-AMP (Imicrocurie/μl). 7/5 ZRA pellets in solution are prepared by adding 500mg to 28ml of H2oO to a final concentration of 20mg/ml of granules and 18mm of zinc sulfate.

The obtained results are shown in table 1 in o yu 1 in in that with m « 1 Z s g what

B. - 1 2) 20 The results shown in Table 1 indicate that the compounds of formula (I) are effective inhibitors of phosphodiesterase 4 (POE 4). The preferred derivatives of pyridazin-3(2H)-one according to the present invention are characterized by an IC value in relation to the inhibition of POE4 activity (determination is carried out as indicated above), which is less than 100 nm, preferably less than 5 nm, and most preferably is less than 2OnM, the compounds are also able to block the production of some pro-inflammatory cytokines, such as TNF-α. 29 Thus, the compounds can be used for allergic, inflammatory and immunological treatment

F! diseases, as well as those diseases or disease states in which selective inhibition of POE4 activity and blocking of pro-inflammatory cytokines are known to be beneficial. Such disease states include | see, for example, patents 5 5449686, 05 5710170, published international applications UUO 98/45268, MO 99/06404, MO 01/57025, MO 01/57036, MO 01/46184, MO 97/05105 , M/o 96/40636, patents OB 5786354, OB 5773467, 05 60 5753666, 05 5728712, 05 5693659, 5 5679696, Z 5596013, Z 5541219, 05 5508300, 05 550 550 or article

N. U. Ouke and 9. b. Mopiapa, Ehr. Orip. Ipmezi. Yugidve, 1999, m.8, p.1301-1325) diseases such as asthma, chronic obstructive pulmonary disease, allergic rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, bone formation disorders, glomerulonephritis, multiple sclerosis, ankylosing spondylitis, Graves' ophthalmopathy ( (Zhamev), asthenic bulbar paralysis, diabetes insipidus, transplant rejection, diseases of the gastrointestinal tract, such as ulcerative colitis or Crohn's disease, septic shock,

respiratory distress syndrome in adults, and skin diseases such as atopic dermatitis, contact dermatitis, acute dermatomyositis and psoriasis. These compounds can also be used to improve cerebrovascular activity, as well as to treat other diseases related to the CNS, such as dementia, Alzheimer's disease, depression, and as nootropic agents.

The phosphodiesterase 4 inhibitors of the present invention may also be useful when administered in combination with other drugs such as steroids and immunosuppressive agents such as cyclosporin A, rapamycin, or T-cell blockers. In this case, the introduction of compounds allows you to reduce the dosage of other drugs, thereby preventing the manifestation of unwanted side effects, characteristic of both steroids and immunosuppressants.

Similar to other phosphodiesterase 4 (POE4) inhibitors (see above references), the compounds of the present invention can also be used to block the ulcerogenic effects induced by many etiological agents, for example, such as anti-inflammatory drugs (steroidal and non-steroidal anti-inflammatory agents) , stress, ammonia, ethanol and concentrated acids. The compounds according to the present invention can be used alone or in combination with antacids and/or antisecretory drugs in the prevention and/or radical treatment of pathologies of the gastrointestinal tract, such as drug-induced ulcers, peptic ulcers, ulcers, associated with N. Ruyogi, esophagitis and diseases caused by gastroesophageal (gastric-esophageal) reflux.

The compounds of the present invention can also be used to treat pathological conditions in which cell or tissue damage is produced by conditions such as oxygen starvation or excess free radicals. Examples of such healing effects are protective effects on heart tissue after coronary artery occlusion or prolongation of cell and tissue viability when the compounds of the present invention are added to preservation solutions intended for storage of organs or fluids, such as blood or semen. Compounds of the present invention may also be useful for tissue regeneration and wound healing.

Accordingly, another variant of the invention is the use of pyridazin-3(2H)-one derivatives (8) of formula (I) for the manufacture of medicinal products intended for the treatment of painful conditions or diseases that are amenable to treatment by inhibition of phosphodiesterase 4 (POE4), as well as a method of treating a patient who is susceptible to a disease state or disease amenable to treatment by inhibition of phosphodiesterase 4 (POE4), the method comprising administering to said patient an effective amount of a compound of formula (1). at

The present invention also relates to a pharmaceutical composition that includes as an active ingredient at least one pyridazin-3(2H)-one derivative of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier, such as a filler or diluent. The active ingredient can be - from 0.00195 to 9995 by weight, preferably from 0.0195 to 9095 by weight of the composition, depending on the nature of the composition and it - depending on the dilutions that were used earlier, before filing the application. Preferably, the compositions are prepared in a form suitable for oral, topical, nasal, rectal, transdermal or injection administration.

Pharmaceutically acceptable excipients, which are mixed with an active compound or a salt of such a compound to obtain the composition according to the present invention, are well-known in themselves and actually used excipients are chosen, including, depending on the intended method of administration of the composition. ;" Compositions for oral administration may be tablets, sustained-release tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powders for inhalation, or liquid preparations such as mixtures, elixirs, syrups, or suspensions that contain the compound. according to this -I invention; such preparations may be prepared using techniques well known in the art.

Diluents which may be used in the preparation of the composition include such liquid and solid diluents as are compatible with the active ingredient, together with coloring agents and flavor and odor enhancing agents, if desired. Tablets or capsules may suitably contain from 2 to 500 mg of the active ingredient or an equivalent amount of its salt.

A liquid composition suitable for oral administration may be in the form of a solution or suspension. These solutions can be aqueous solutions of a soluble salt or another derivative of an active compound in combination, for example, with sucrose to obtain a syrup. Suspensions may include an insoluble active compound of the present invention or a pharmaceutically acceptable salt thereof in combination with water, together with a suspending agent and a taste and odor enhancing agent.

F) Compositions for parenteral injections can be obtained from soluble salts, which can be lyophilized or not dried and which can be dissolved in a pyrogenic aqueous medium or other liquid medium suitable for parenteral injections. Compositions for topical administration may be in the form of ointments, creams or lotions containing a compound of the present invention; such preparations can be prepared according to techniques known from the prior art.

Effective doses are usually in the range of 10-600 mg of the active ingredient per day. Daily dosages can be administered in one or more doses, preferably from 1 to 4 doses per day. 65 Next, this invention will be illustrated by examples. The examples given are for illustration purposes only and should not be construed as limiting the scope of the invention.

Nuclear magnetic resonance H spectra are recorded on a Magap Setipi 300 spectrometer. Low-resolution mass spectra (pt/72) are recorded on a Misgotazz 2MO mass spectrometer using electrospray ionization (E5I). The melting temperature is determined on a Regkip EIteg device О5С-7". Chromatographic separation is carried out using the Umayege 2690 zuviet system, equipped with a Zutteyu C18 column (21x10 mm, 3.5 mm). The mobile phase is formic acid (0.4 ml), ammonia (0.1 ml), methanol (500ml) and acetonitrile (500Oml) (B) and formic acid (0.4bml), ammonia (0.115ml) and water (100Oml) (A): first from 090 to 9590 phase B for 2h, and then 4min. from 9595 of phase B. The time to restore equilibrium between two introductions of the sample under investigation is two minutes. The flow rate is O0.4ml/min. The volume of the sample introduced is 5 microliters. A diode matrix is used to record the chromatogram at 21O0nM.

Preparatory examples

Preparatory example 1 1-(3-"Cyclopentyloxy)-4-methoxyphenyl|butane-1,3-dione

While stirring, a solution of (1-3-cyclopentyloxy)-4-methoxyphenyl-ethanone is gradually added to a suspension of sodium hydride (200 mg, 5 mmol) and ethyl acetate (0.49 ml, 5 mmol) in 75 tetrahydrofuran (25 ml).

European patent application EP470805) (590 mg, 2.5 mmol) in tetrahydrofuran (bml), two drops of ethanol and a solution of dibenzo-18-crown (15 mg, 0.04 mmol) in tetrahydrofuran (ml). The reaction mixture is refluxed for 5 hours, allowed to cool to room temperature, and the reaction is finally stopped by adding a 1095 aqueous solution of sulfuric acid (5 ml). The resulting mixture is diluted with diethyl ether, washed with a saturated solution of ammonium chloride, dried and concentrated under reduced pressure, thus obtaining a crude product, which is purified by column chromatography (5% O»o, a mixture of hexane - ethyl acetate in the ratio 4:1), thus obtaining the indicated in the title compound (6b1Omg, output 8690) in the form of a light yellow oily substance. 5(SOCI3): 1.62 (t, 2H), 1.85 (t, 6H), 2.16 (85, ЗН), 3.98 (v, ЗН), 4.82 (t, 1Н), 6,10 (in, 1H), 6854, p

LN), 7.42 (t, 2H). at

Preparatory example 2

Ethyl ether of 5-methyl-4-I4-(methylthio)benzoylisoxazole-3-carboxylic acid

To an ice-cooled solution of sodium ethoxide (3.2g, 5X9ummol) in absolute ethanol (125ml) is added in portions 1-(4-(methylthio)phenyl|butane-1,3-dione (|Soegii», (., Nagytapp, N. Heteroai. Spet., 1997, M.8, pp. p.147-55) (11.2g, 54mmol), and the resulting mixture is stirred at 02 for 30h. A solution of ethyl ether of chloro(hydroxyimino)acetic acid (9, 0g, 59mol) in absolute ethanol (25ml), and this mixture was stirred at room temperature overnight. The resulting mixture was acidified with 5-6% acetic acid and concentrated. The residue obtained in this way was partitioned between ethyl acetate and water, washed m saturated salt solution, dried and concentrated under reduced pressure, thus obtaining the title compound (13.Og, yield 70905) in the form of a yellow solid. 2.56 (c, 6H), 4.07 (a, 2H), 7.42 (a, 2n), 7.65 (a, 2H).

Preparatory example Z

Ethyl ether of 4-(33-(cyclopentyloxy)-4-methoxybenzoyl|-5-methylisoxazole-3-carboxylic acid "

The title compound is obtained as a yellow solid (yield 9190) from 1-(3-cyclopentyloxy)-4-methoxyphenyl|butane-1,3-dione (preparative example 1) and chloro(hydroxyimino)acetic acid ethyl ether acid according to the experimental method described in preparatory example 2. ), 3.98 (v, 3H), 4.07 (a, 2H), 4.82 (t, " 1H), 6.85 (4, 1H), 7.23 (j, 1H), 7, 42 (8, 1H).

Preparatory example 4

4-(4-Fluorobenzoyl)-5-methylisoxazole-3-carboxylic acid ethyl ether - The title compound (yield 9595) is prepared from 1-(4-fluorophenyl)butane-1,3-dione Ovi, K.S.; Raipak, -1 M.M.; bye, Sho. 9. Ipdiap Spet. wasps 1983, m. 60, p. 1074-1076)| and ethyl ether of chloro(hydroxyimino)acetic acid according to the experimental method described in preparatory example 2. about 9(SOCIv): 1.1 (6 ЗН), 2.50 (5, ЗН), 4.20 (а, 2Н ), 7.20 (t, 2H), 7.80 (t, 2H). o 70 Preparatory example 5

Ethyl ether of 4-(33-fluorobenzoyl)-5-methylisoxazole-3-carboxylic acid g». ; Raipak,

M.M.; bag, M. U. Ipaiai Spet. Bos, 1983, m. 6b0, 1074-1076)| and ethyl ether of chloro(hydroxyimino)acetic acid according to the experimental method described in preparatory example 2. 29 9(SOCIv): 1.10 (Yii, ZN), 2.60 (v, ZN), 4.15 (ad, 2H), 7.30 (t, 4H). (FI Preparatory example 6

Ethyl ether of 4-benzoyl-5-propylisoxazole-3-carboxylic acid o The compound indicated in the title (yield 70956) is obtained from 1-phenylhexane-1,3-dione (I emipe ei ai., U. Ateg.

Spent boss, 1945, m. 67, r. 1510| and ethyl ether of chloro(hydroxyaminoacetic acid according to the method of the experiment described in preparatory example 2. 9(SOCI"): 1.00 (i, 6H), 1.80 (t, 2H), 2.90 (Ii, 2H ), 4.10 (ad, 2H), 7.50 (t, 5H).

Preparatory example 7

3-Methyl-4-4-(methylthio)phenylisoxazolo|3,4-4|Ipyridazin-7(6H)-one

Hydrazine monohydrate (1.70 g, 5 mmol) was added dropwise to a solution of the title compound of Preparative Example 2 (7.11 g, 23 mmol) in dry ethanol (50 mL), and then the resulting mixture was stirred overnight. After cooling in an ice bath, a precipitate formed, which was collected by filtration and washed with diethyl ether to give the title compound (3.31 g, yield 53905) as a yellow solid. 9(SOSI"): 2.57 (8, ЗН), 2.58 (c, ЗН), 7.25 (y, 2Н), 7.42 (a, 2Н), 11.35 (b, 1Н) .

Preparatory example 8 4-I(IZ--"Cyclopentyloxy)-4-methoxyphenyl|-3-methylisoxazoloi33,4-4|pyridazin-7(6H)-one

The title compound is obtained as a yellow solid (yield 93905) from the compound indicated in the title of Preparative Example 3, according to the experimental method described in Preparatory Example 7. 70 З(СОСИв): 1.61-2.01 (t .

Preparatory example 9 4-(4-Fluorophenyl)-3-methylisoxazoloi|Z,4-4|Ipyridazin-7(6H)-one

The title compound (yield 8795) is obtained from the compound indicated in the title of Preparatory Example 4, according to the experimental method described in Preparatory Example 7. 9(SOCI"): 2.55 (in, ЗН), 7.30 (t , 2H), 7.60 (t, 2H).

Preparatory example 10 4-(3-Fluorophenyl)-3-methylisoxazoloi|3,4-4|pyridazin-7(6H)-one.

The title compound (81956) is obtained from the title compound of Preparatory Example 5, according to the experimental method described in Preparatory Example 7. 9(SOCI"): 2.60 (in, ЗН), 7.3 (t, 4H), 9.90 (in, 1H).

Preparatory example 11 4-Phenyl-3-propylisoxazolo!|3,4-a|pyridazin-7(6H)-one

The compound specified in the title (yield 4095) is obtained from the compound specified in the title of Preparatory Example b, according to the experimental method described in Preparatory Example 7. t, 2H), 2.80 (i, 2H), 7.50 (t, 5H), 10.0 (c, 1H). (5)

Preparatory example 12 6-Ethyl-3-methyl-4-(4-(methylthio)phenylisoxazolo!|Z,4-4|pyridazin-7(6H)-one

Cesium carbonate (17.2 g, 53 mmol) was added to a solution of the compound indicated in the title of Preparative Example 7 (2.4 g, 8.8 mmol) in dry dimethylformamide (3 mL), and then the resulting suspension was stirred for 15 s minutes. Then ethyl bromide (4.bml, b2mmol) is added dropwise and the resulting mixture is stirred at room temperature overnight, and then at 502C for 5 hours. The mixture is concentrated and the residue obtained in this way is suspended in ethyl acetate, washed with water and a saturated salt solution, dried and concentrated, obtaining the title compound (1.44 g, yield 5495) as a yellow solid. ): 1.38 (i, ЗН), 2.57 (в, ЗН), 2.58 (8, ЗН), 4.23 (а, 2Н), 7.35 (а, 2Н), 7.48 (a, 2H).

Zo Preparative example 13 - 6-Ethyl-4-(4-(methylthio)phenyl|-3-propylisoxazolo!|3,4-4|pyridazin-7(6H)-one

When stirring, a solution of sodium hydroxide (0.43 g, 10 mmol) in dry dimethylformamide (ml) is added to a solution of the compound specified in the title of preparatory example 7 (1.5 g, 5.4 mmol) in dry dimethylformamide (1 ml). and the resulting mixture is stirred for 15 minutes. Ethyl bromide (1.21 mL, 16.2 mmol) was then added dropwise, and the mixture was stirred at room temperature for 2 h, poured into dichloromethane and washed with water and brine. The organic layer is dried and the solvent is removed, obtaining the crude product, which is purified by express column chromatography (5105, a mixture of hexane - ethyl ether in the ratio 4:11), thus obtaining the title compound (0.20 g, yield 1296). 9(SOSI"): 0.82 (i, ЗН), 1.39 (I, ЗН), I ba(t, 2Н), 2.57 (в, ЗН), 2.82 (Б 2Н), 4 .23 (a, 2H), 7.35 (a, 2Hn), 7.42 (a, 2Hn). it. Preparatory example 14-I 6-Ethyl-3-(1-ethylpropyl)-4-I(4-(methylthio)phenyl)-isoxazolo|3,4-4|pyridazin-7(6H)-one

The title compound is obtained as a by-product (yield 795) in Preparative Example 13. i-y 9(SOCI"): 0.62 (i, 6H), 1.39 (i, ЗН), 1.75 (t , 4H), 2.59 (c, 3H), 2.78 (t, 1H), 4.24 (a, 2H), 7.38 (t, 4H). o 250 Preparative example 15 6-Ethyl-3-methyl-4-(4-(methylsulfinyl)phenylisoxazolo|3,4-4|pyridazin-7(6H)-one iz When stirring to an ice-cooled solution of the compound indicated in the title of the preparatory of example 12 (1.0g, 3.32mmol), in methanol (dml) a solution of sodium periodate (0.71g, 3.3mmol) in water (vml) is added dropwise. The resulting mixture is stirred at 02C for 2 hours and then at at room temperature overnight. 59 The solvent was removed and the resulting slurry was suspended in water and then extracted with ethyl acetate.The organic layer

HF) is dried, after which the solvent is removed, thereby obtaining the title compound (0.70 g, yield

HF 66) in the form of a light yellow solid. 9(SOSIv): 1.42 (i, ЗН), 2.57 (в, ЗН), 2.81 (8, ЗН), 4.30 (ad, 2Н), 7.75 (а, 2Н), 7.85 (a, 2H). in Preparatory example 16 4-I(3-"Cyclopentyloxy)-4-methoxyphenyl|-b-ethyl-3-methylisoxazoloi3,4-4|pyridazin-7(6H)-one

The title compound (yield 3895) was obtained from the title compound of Preparative Example 8, according to the experimental method described in Preparatory Example 12. , 2H), 1.91 (t, 6H), 2.58 (c, 3H), 3.98 (c, 3H), 4.17 (a, 2H), 4.83 (t, 1H), 7 ,03 (t, ZN). 65 Preparatory example 17 6-Ethyl-4-(4-fluorophenyl)-3Z-methylisoxazolo!|Z,4-4|pyridazin-7(6H)-one

Ethyl bromide (0.44g, 4.0mmol) was added to a suspension of the compound indicated in the title of Preparative Example 9 (0.49g, 2.00mmol) and anhydrous potassium carbonate (0.55g, 4.0mmol) in dry dimethylformamide (5.3ml). O0mmol), after which the resulting mixture is heated at 11092 for 40 minutes. Ice water (3 mL) was then added and the resulting precipitate was collected by filtration to give the title compound (0.47 g, yield 8695) as a yellow solid. 9(SOSIv): 1.40 (i, ЗН), 2.58 (в, ЗН), 4.23 (а, 2Н), 7.20 (t, 2Н), 7.58 (t, 2Н).

Preparatory example 18 6-Ethyl-4-(3-fluorophenyl)-3Z-methylisoxazolo!|Z,4-4|pyridazin-7(6H)-one

The title compound (yield 8495) is obtained from the title compound of Preparative Example 10 according to the experimental method described in Preparatory Example 17. , ЗН), 4.30 (a, 2Н), 7.30 (t, ЗН), 7.50 (t, 1Н).

Preparatory example 19 6-Ethyl-4-phenyl-3-propylisoxazol!|3,4-4|pyridazin-7(6H)-one

The title compound (yield 9095) is obtained from the title compound of Preparative Example 11, according to the experimental method described in Preparatory Example 17. i, ZN), 1.80 (t, 2H), 2.80 (t, 2H), 4.25 (t, 2H), 7.50 (8, 5H).

Preparation example 20 6-"Cyclopropylmethyl)-3-methyl-4-phenylisoxazolo!|Z,4-a|pyridazin-7(6H)-one

The title compound is obtained as a light brown solid (yield 7095) from

Z-methyl-4-phenylisoxazolo|3,4-4|Ipyridazin-7/(6H)-one (Kepli, (0. Ripgations, 5., | BRagptaso a. zsi., 1969, m. 24, p. 885 -889)| and cyclopropyl methyl bromide according to the experimental method described in preparatory example 17. 9(СОСИ"): 0.42 (t, 4Н), 1.38 (t, 1Н), 2.55 (в, ЗН), 4.08 (a, 2H), 7.61 (t, 5H). Gee!

Preparatory example 21 o

3-Methyl-4-phenyl-b-(pyridin-4-ylmethyl)isoxazolo!|3,4-4|pyridazin-7(6H)-one

When stirring to a suspension of 3-methyl-4-phenyl-isoxazolo|3,4-4|Ipyridazin-7/(6H)-one (1.5 g, b,bmmol)

I (Kepli, 0.; Replgations, 5., IYI Ragtaso Ed. 5si., 1969, m.24, p.885-889), add 6bO95 sodium hydride (0.63g, 15.8mmol) in portions and the obtained the mixture is stirred for 15 minutes. Then 4-(chloromethyl)pyridine hydrochloride (1.3 g, 7.9 mmol) was added in portions, and the resulting mixture was stirred at 50922 for 7 hours, then poured into water and extracted with ethyl acetate. The organic layer is washed with a saturated salt solution, dried and concentrated in a vacuum, obtaining the crude product, which is recrystallized from (M mixture of isopropyl ether/petroleum ether, obtaining the title compound (1.66 g, yield 79905) in the form of a clear - brown solid. 9(SOSI"): 2.55 (8, ЗН), 5.38 (5, 2Н), 7.38 (9, 2Н), 7.57 (t, 5Н), 8.58 (t, 2H). -

Preparatory example 22 5-Acetyl-4-amino-2-ethyl-6-phenylpyridazin-3(2H)-one

A mixture of b-ethyl-3-methyl-4-phenylisoxazolo|3,4-4|Ipyridazin-7(6H)-one (Oa! Ria7, Mei ai, U. Mei. Spet., 1997, " m. 40, r.1417) (2.0g, 7.8Zmmol) and 1096 palladium on carbon (400mg) in ethanol (400ml) are shaken in a hydrogen atmosphere at room temperature and a pressure of 2 bar for 3 hours. The catalyst was filtered off and the solvent was removed under reduced pressure to give the title compound (1.97 g, yield 9895). "» T.pl. 150.8-152.72С " 9(SOSI"): 1.43 (i, ЗН), 1.67 (rev, 2Н), 1.78 (5, ЗН), 4.26 (4, 2H), 7.45 (c, 5H).

Preparative example 23 15 5-Acetyl-4-amino-2-ethyl-6-(4-(methylthio)phenyl|pyridazin-3(2H)-one and A mixture of the compound specified in the title of preparative example 12 (0.5g, 1 .6bmmol), 1090 palladium on - | carbon (1Omg) and ammonium formate (2.3g, ZOmmol) in ethanol (2Oml) were refluxed overnight. An additional amount of catalyst (213mg) was added and the resulting mixture was boiled refluxed for another 24 hours. Finally, the catalyst was filtered off, after which the solvent (9) 50 was removed under reduced pressure. The resulting residue was purified by flash column chromatography (510 5, dichloromethane) to give the title product compound (190Omg, yield 37905). iz 9(SOSIv): 1.42 (, ЗН), 1.81 (в, ЗН), 2.50 (8, ЗН), 4.24 (а, 2Н), 7 ,35 (t, 4H).

Preparative Example 24 4-Amino-5-butyryl-2-ethyl-6-I4-(methylthio)phenyl|Ipyridazin-3(2H)-one 59 The title compound (yield 2795) is obtained from the compound indicated in the title of the Preparative Example

HF) 13, according to the method described in preparatory example 23. 7 9(SOSI"): 0.65 (Y, ЗН), 1.39 (t, 5Н), 2.02 (и, 2Н), 2.50 (c, ЗН), 4.23 (а, 2Н), 7.12 (р5,2Н), 7.35 (t, 4Н).

Preparatory example 25 in 4-Amino-2-ethyl-5-(2-ethylbutanoyl)-6-I(4-(methylthio)phenyl|pyridazin-3(2H)-one

The title compound (yield 5695) was obtained from the title compound of Preparative Example 14 by the method described in Preparative Example 23. 7H), 2.10 (t, 1H), 2.51 (v, 3H), 4.24 (a, 2H), 7.01 (rv, 2H), 7.38 (t, 4H).

Preparatory example 26 65 5-Acetyl-4-amino-2-ethyl-6-(4-(methylsulfinyl)phenyl|pyridazin-3(2H)-one

The title compound (7095) is obtained from the title compound of Preparative Example 15 by the method described in Preparatory Example 23. 9(SOCIv): 1.41 (i, ЗН), 1.80 (в, ЗН), 2.77 (c, ЗН), 4.30 (а, 2Н), 7.65 (а, 2Н), 7.77 (9, 2Н).

Preparatory example 27 5-Acetyl-4-amino-6-(3-dicyclopentyloxy-4-methoxy-phenyl)-2-ethylpyridazin-3(2H)-one

The title compound (yield 4095) is obtained from the title compound of Preparative Example 16 by the method described in Preparative Example 23. 9(SOCIs): 1.42 (His, ZN), 1.61-2.01 ( t, 11Н), 3.98 (v, ЗН), 4.23 (а, 2Н), 4.83 (t, 1Н), 6.98 (t, ЗН), 7.32 (вв, 2Н).

Preparatory example 28 5-Acetyl-4-amino-2-benzyl-b6-phenylpyridazin-3(2H)-one

The title compound (yield 9296) was prepared from b-benzyl-3-methyl-4-phenylisoxazolo!|3,4-4|Ipyridazin-7(6H)-one |Oai! Ria;, M.; Sisiapi, (3.; (ziomappopi, M.R.,

ERagtaso, 1991, M.46, pp. 435-47) according to the method described in preparatory example 23. 9(СОСИ"): 1.78 (in, ЗН), 5.38 (in, 2Н), 7.21 -7.55 (t, 10N).

Preparatory example 29 5-Acetyl-4-amino-2-(cyclopropylmethyl)-b-phenylpyridazin-3(2H)-one

The title compound (9095) is obtained from the title compound of Preparative Example 20 by the method described in Preparative Example 23. 9(SOCIv): 0.51 (t, 4H), 1.40 (t, 1H), 1.78 (c, ЗН), 4.02 (a, 2Н), 7.43 (t, 5Н).

Preparatory example 30 5-Acetyl-4-amino-6-phenyl-2-(pyridin-4-ylmethyl)pyridazin-3(2H)-one

The title compound (yield 8595) is obtained from the title compound of Preparative Example 21 by the method described in Preparative Example 23. 9(SOCIv): 1.77 (8, ЗН), 5.36 (in, 2Н) , 7.27 (0, 2H), 7.43 (t, 5H), 8.59 (a, 2H). Gee!

Preparatory example 31 about 5-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-nitropyridazine-Z3(2H)-one

To the suspension of the compound specified in the title of preparatory example 17 (0.5g, 1.83mmol) in a mixture of acetic acid (7.3ml), water (7.3ml) and nitric acid (2.5ml), nitrate is added in portions while stirring cerium and ammonium (6b, 0g, 1immol) for 40 minutes. After the addition of ice water, a precipitate is formed from the crude substance, which is filtered and washed with cold water, thereby obtaining the compound indicated in the title (yield 45965). 9(SOSIv): 1.43 (Her, ZN), 2.20 (in, ZN), 4.40 (ad, 2H), 7.20 (t, 2H), 7.48 (t, 2H). iv)

Preparatory example 32 im- 5-Acetyl-2-ethyl-6-(3-fluorophenyl)-4-nitropyridazine-Z3(2H)-one

From The compound indicated in the title (4095) is obtained from the compound indicated in the title of Preparative Example 18, c. in accordance with the experimental method described in preparatory example 31. 9(SOCIv): 1.50 (i, ЗН), 2.20 (в, ЗН), 4.40 (а, 2Н), 7.20 (t, ЗН ), 7.46 (t, 1H).

Preparatory example 33 "

Butyryl-2-ethyl-4-nitro-6-phenylpyridazin-Z3(2H)-one

The compound indicated in the title (yield 5195) is obtained from the compound indicated in the title of Preparatory Example C p 19, according to the experimental method described in Preparatory Example 31. 1.50 (t, 5H), 2.35 (t, 2H), 4.40 (ad, 2H), 7.50 (t, 5H). "Preparative example 34 6-Ethyl-3,4-diphenylisoxazoliZ, 4-4|pyridazin-7(6H)-one

The title compound was obtained as a solid (yield 9190) from this. Z,4-diphenylisoxazoloi|Z,4-4|Ipyridazin-7(6H)-one |Keplgi, 0.; Yua! Riag, Bali. SPP M 1965, m.95, r.1478-911 -I and ethyl bromide according to the experimental method described in preparatory example 17. 9(СОСИ"): 1.40 (i, ЗН), 4.38 (ad, 2Н) , 7.35 (t, 10OH). i-th Preparatory example 35 (4) 50 4-Amino-5-benzoyl-2-ethyl-6-phenylpyridazin-3(2H)-one

The title compound (yield 9095) is obtained from the title compound of Preparative Example 34 by the method described in Preparative Example 22. 9(SOCI"): 1.43 (His, ZN), 4.38 (a, 2H), 6.88 (in, 2H), 7.10 (t, 4H), 7.24 (t, ЗН), 7.43 (t, ЗН).

Preparatory example 36 59 5-Amino-1-ethyl-6b-oxo-3-phenyl-1,6-dihydropyridazine-4-carbaldehyde

GF) Mixture // 5-amino-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carbaldehyde-one |Oai Ria7, M., Sisiapi, o, 7 Siomappopi, M.R., Neyegosusiev, 1991 , m. 32, r. 1173-9| (258mg, 1.2mmol), ethyl bromide (294mg, 2.7mmol) and anhydrous potassium carbonate (240mg, 2.4mmol) in anhydrous DMF (ml) were stirred at 902C for 2 hours. Cold water (25ml) is added and the precipitate formed is collected by filtration, thereby obtaining the title compound (yield 88965). 9(SOSIv): 1.43 (Y, ЗН), 4.27 (t, 2H), 6.95 (v, 2H), 7.48 (t, 5H), 9.75 (8, 1H).

Preparatory example 37

Ethyl ether of 4-benzoyl-5-hydroxyoxazole-3-carboxylic acid 65 While stirring, a solution of ethyl benzoyl acetate (9.6 g , 0 O0bmol) in the same solvent (b5ml). A solution of chloro(hydroxyimino)acetic acid ethyl ether (7.55 g, O0.05 mol) in anhydrous EN (10 ml) was added dropwise (within 1 hour). The resulting mixture is neutralized using a 6N solution

NS, then the alcohol layer is evaporated. After diluting with cold water (150-200 ml), the suspension is extracted with ethyl ether and then the aqueous layer is acidified using a 6N HCl solution, thereby obtaining a product that is isolated by filtration (yield 4590). 9DMSO-a c): 1.25 (Y, ЗН), 4.15 (а, 2Н), 7.50 (t, ЗН), 7.80 (t, 2Н), 10.80 (5, 1Н) .

Preparatory example 38

5-Amino-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid methyl ester 70 A mixture of the compound indicated in the title of Preparative Example 37 (200mg, 0.7bmmol), hydrazine hydrate (165mg,

C,3mmol), PPA (polyphosphoric acid (12 g) and 12 ml of anhydrous EN are stirred at 402 for 12 hours.

After dilution with water (40 ml), the crude precipitate is isolated by vacuum filtration. Then the obtained substance is suspended in 2 ml of EUN and ammonium formate (75 mg, 1.2 mmol) and 1096 Ra/s (15 mg) are added. The resulting mixture is boiled under reflux for 1 hour. After filtration and evaporation of solvent 75, the product is obtained, which is dissolved in anhydrous DMF (1.7 ml). Add anhydrous potassium carbonate (5Omg,

0,bmmol) and iodomethane (20Omg, 1.4mmol) and the resulting mixture is stirred at room temperature for 45 minutes.

Cold water (2Oml) is then added and the title compound is collected by filtration (yield 5090). 9(SOSI"): 3.49 (in, ЗН), 7.02 (8, 2Н), 7.38 (in, 5Н).

Preparatory example 39

5-Amino-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid methyl ester

To a mixture of the title compound of Preparative Example 38 (122 mg, 0.5 mmol) and anhydrous potassium carbonate (14 mg, 1.4 mmol) in anhydrous DMF (1.4 mL) was added ethyl bromide (0.1 mL, 1.2 mmol) and then reflux under stirring for 1 hour. The suspension was diluted with cold water and the title compound was collected by filtration (yield 7590). c 9(SOSIv): 1.41 (i, ЗН), 3.48 (5, ЗН), 4.25 (а, 2Н), 7.00 (c, 2Н), 7.38 (c, 5Н) . at

Preparatory example 40 6-Ethyl-4-phenyl-3-styryl-bH-isoxazolo!|3,4-4|pyridazin-7-one

To a freshly prepared solution of sodium methoxide (108 mg, 1.9 mmol) in methanol (2 ml) is added a solution of b-ethyl-3-methyl-4-phenyl-bH-isoxazolo|3,4-4|pyridazin-7-one (500 mg, 1 .9bmmol) |Oh! Ria?, M.; Siomapopi, M. M

R., SavieMNapa, S; ей аиЙ., 9У. Honey. Spet., 1997, m. 40, r. 1417-1421)| in 2 ml of dry methanol, and the resulting mixture is stirred for some time. Then benzaldehyde (0.4 Oml, 3.92 mmol) was added dropwise, and the resulting mixture was refluxed for 2 hours. The resulting suspension was allowed to cool and then the target product (514 mg, yield 7695) was collected by filtration. M 9(SOSI"): 1.40 (, ЗН), 4.31 (4, 2Н), 6.80 (а, 1Н), 7.35 (t, 5Н), 7.68 (t, 6Н) .

Preparatory example 41-6-Ethyl-4-phenyl-3-(2-thiophen-3-yl-vinyl)-6H-isoxazolo!|3,4-4|pyridazin-7-one

The title compound (yield 7590) was prepared from b-ethyl-3-methyl-4-phenyl-bH-isoxazolo!|3,4-4|pyridazin-7-one (5000 mg, 1.9 mmol) |Oa! Riag, M.; biomappopi, M. «

R.; SavzieMapa, S.; hey a), 9). Honey. Spet., 1997, m. 40, p. 1417-1421) and thiophene-3Z-carbaldehyde according to the method described in preparatory example 40. - c 9(SOSI"): 1.42 (i, ЗН), 4.30 (a, 2H), 6.58 (a, 1H), 6.98 (a, 1H), 7.28 (t, 1H), 7.42 (t, 1H), 7.63 (t, 6H) . "» Preparative example 42 " 6-Ethyl-4-phenyl-3-(2-pyridin-3-ylvinyl)-6H-isoxazolo!|Z,4-hy|pyridazin-7-one

The title compound (yield 7096) was prepared from β-ethyl-3-methyl-4-phenyl-bH-isoxazolo|3,4-4|pyridazin-7-one (500mg, 1.9bmmol) |Oa! Riag, M.; Siomapopi, M. - R.; Savieyapa, S; her aI.,, 9). Honey. Spet., 1997, m. 40, r. 1417-1421| and pyridine-33-carbaldehyde according to the method described in Preparatory Example 40. .88 (in, 1H), 7.50-7.66 (t, 7H), 8.60 (in, 2H). o Preparatory example 43

Ha 50 4-Amino-2-ethyl-b6-phenyl-5-(3-phenylpropionyl)/pyridazin-3(2H)-one

A mixture of the compound indicated in the title of Preparative Example 40 (514mg, 1.50mmol) and 1090 palladium on g" carbon (10Omg) in ethanol (10Oml) was shaken under a hydrogen atmosphere at room temperature and a pressure of 2 bar overnight. The catalyst was filtered off, after which the solvent was removed under reduced pressure to give the title compound (487 mg, yield 9590). 29 T. pl. 115.1-116.12С

HF) 9(SOSIv): 1.40 (Ii, ZN), 2.28 (i, 2H), 2.68 (I, 2H), 4.25 (a, 2H), 6.78 (t, 2H ), 7.05 (t, ZN), 7.45 (t, 5H). t Preparatory example 44 4-Amino-2-ethyl-b-phenyl-5-(3-thien-3-ylpropanoyl)pyridazin-3(2H)-one

The compound indicated in the title (yield 6795) is obtained from the compound indicated in the title of Preparative Example 60 41, according to the method described in Preparatory Example 43. 9(SOCIv): 1.41 (i, 3H), 2.30 (i, 2H ), 2.70 (i, 2H), 4.25 (a, 2H), 6.08 (y, 1H), 6.54-6.62 (t, 2H), 7.08-7.58 ( t, 7H).

Preparatory example 45 4-Amino-2-ethyl-b-phenyl-5-(3-pyridin-3-ylpropanoyl)pyridazin-3(2H)-one

The title compound (yield 9795) is obtained from the title compound of Preparative Example 42 by the method described in Preparative Example 43.

9(SOSIv): 1.41 (its, ЗН), 2.29 (I, 2Н), 2.70 (0 2Н), 4.25 (a, 2Н), 7.05-7.57 (t, 9H).

Preparatory example 46 6-Isopropyl-3-methyl-4-phenyl-bH-isoxazolo!|Z3,4-4|pyridazin-7-one

To a stirred solution of Z-methyl-4-phenylisoxazolo|Z,4-4|Ipyridazin-7(6H)-one (0.5 g, 2.2 mmol) |Kept?gi,

About. Ripgations, 95., | Bragptaso Ay. Si, 1969, mu.24, p.885-889), triphenylphosphine (0.577g, 2.2mmol) and isopropanol (0.170ml, 2.2mmol) in 7ml of dry THF add diethylazadicarboxylate (0.345mml, 2.2equiv.) dropwise. ), and the resulting mixture is stirred at room temperature overnight. The solvent is then removed and the product obtained is purified by express column chromatography (500, hexane - ethyl acetate), thereby obtaining the title compound (374 mg, yield 63905). 9(SOSI"): 1.42 (d, 6H), 2.58 (v, ЗН), 5.40 (t, 1H), 7.55 (t, 5H).

Preparatory example 47 5-Acetyl-4-amino-2-isopropyl-b6-phenylpyridazin-3(2H)-one

The title compound (yield 9295) is obtained from the title compound of Preparative Example 75 46 by the method described in Preparative Example 23. 9(SOCI"): 1.40 (9, 6H), 1.78 (8, ЗН ), 5.32 (t, 1H), 7.45 (t, 5H).

Preparatory example 48 6-(2-Hydroxyethyl)-3-methyl-4-phenyl-bH-isoxazolo|Z,4-4|pyridazin-7-one

The title compound is obtained as a solid (yield 9890) from

Z-methyl-4-phenylisoxazolo|Z,4-4|Ipyridazin-7(bH)-one (|Kepli, (.; Riplashi, Z., and Raptaso E. Zsi.,, 1969, m. 24, p. 885-889) and 2-bromomethanol according to the experimental method described in preparatory example 17.

The mixture is stirred at 502C for 5 hours and then the obtained product is isolated by pouring the reaction mixture into water and extracting with ethyl acetate.

З(DMSO-th in): 2.57 (in, ЗН), 3.75 (9, 2Н), 4.18 (Іі, 2Н), 4.83 (і, 1Н), 7.18 (t, ZN), 7.25 (t, 2H). Gee!

Preparatory example 49 about 5-Acetyl-4-amino-2-(2-hydroxyethyl)-b6-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid (yield 9995) from the compound indicated in the title of Preparative Example 48 by the method described in Preparative Example 22. 9DMSO-a in): 1.78 (in, ЗН), 3.72 (I, 2H), 4.18 (, 2H), 7.40 (t, 5H), 7.78 (rz, 2H). with

Preparatory example 50 so 4-(3-Fluorophenyl)-6-(2-hydroxyethyl)-3-methyl-bH-isoxazoloi|3,4-4|pyridazin-7-one

The title compound was obtained as a solid (yield 75905) from the title compound of Preparative Example 10 and 2-bromomethanol according to the experimental procedure described in Preparative Example 17. The mixture was stirred at room temperature overnight and then received

The product is isolated by pouring the reaction mixture into water and extracting with ethyl ether. in.

Mass spectrum (I EM5): t/7 290 (M--1)"

Preparatory example 51 5-Acetyl-4-amino-6-(33-fluorophenyl)-2-(2-hydroxyethyl)-2H-pyridazin-3-one "

The title compound is obtained as a solid (yield 86905) from the compound indicated in the title of Preparative Example 50 by the method described in Preparatory Example 22. o, c Mass spectrum (I EM5): t/72 292 (МА1) " "» Preparatory example 52 " 4-(3-Chlorophenyl)-6-(cyclopropylmethyl)-3-methylisoxazolo (Z,4-4|pyridazin-7(6H)-one

The title compound (yield 6796) was prepared from 4-(3-chlorophenyl)-3-methyl-bH-isoxazolo|3,4-4|pyridazin-7-one (Oal! Rial, Mey aiY., 9. May . Spet. 1997, m. 40, - p. 1417) and cyclopropyl methyl bromide according to the experimental method described in preparatory example 17. -1 The obtained product is purified by column chromatography.

Mass spectrum (I EM5): t/2 316 (M.-1)7. o Preparatory example 53

Ge) 20 5-Acetyl-6-(3-chlorophenyl)-2-(cyclopropylmethyl)-4-nitropyridazin-3(2H)-one

The title compound (2195) is obtained from the title compound of Preparative Example 52 according to the experimental method described in Preparatory Example 31. The obtained product is purified by column chromatography.

Mass spectrum (GAM5): t/2 348 (M-1)7. 25 Preparatory example 54

HF) 6-"Cyclopropylmethyl)-4-(3-fluorophenyl)-3-methylisoxazolo|Z,4-4|Ipyridazin-7(6H)-one 7 The title compound (yield 3795) is obtained from the title compound of preparatory example 10, cyclopropyl methyl bromide according to the experimental method described in preparatory example 17.

The obtained product is purified by column chromatography. bo 9(SOSI"): 0.52 (t, 4H), 1.38 (t, 1H), 2.58 (v, ЗН), 4.07 (а, 2Н), 7.30 (t, ЗН ), 7.55 (t, 1H).

Preparatory example 55 5-Acetyl-2-(cyclopropylmethyl)-6-(3-fluorophenyl)-4-nitropyridazin-3(2H)-one

The title compound (yield 2395) is obtained from the title compound of Preparative Example 54 according to the experimental method described in Preparatory Example 31. 65 9(SOCI"): 0.54 (t, 4H), 1.51 (t , 1H), 2.21 (c, 3H), 4.16 (a, 2H), 7.22 (t, 3H), 7.45 (t, 1H).

Preparatory example 56 4-(3-Fluorophenyl)-6-isopropyl-3-methylisoxazolo!|3,4-a|pyridazin-7(6H)-one

The title compound (yield 3795) is obtained from the title compound of Preparative Example 10 according to the experimental method described in Preparative Example 46. 9(SOCI"): 1.38 (y, 6H), 2.58 (5 , ЗН), 5.41 (t, 1Н), 7.32 (t, ЗН), 7.52 (t, 1Н).

Preparatory example 57 5-Acetyl-6-(3-fluorophenyl)-2-isopropyl-4-nitropyridazin-3(2H)-one

The title compound (yield 4095) was prepared from the title compound of Preparative Example 70.56 according to the experimental procedure described in Preparative Example C1. 9(SOSI"): 1.44 (d, 6H), 2.20 (8, ЗН), 5.45 (t, 1Н), 7.16 (t, ЗН), 7.50 (t, 1Н) .

Preparatory example 58 6-"Cyclopropylmethyl)-4-(4-fluorophenyl)-3-methylisoxazolo|Z,4-4|Ipyridazin-7(6H)-one

The title compound (yield 4695) was prepared from the title compound of Preparative Example 75 9 and cyclopropyl methyl bromide according to the experimental procedure described in Preparative Example 17.

The obtained product is purified by column chromatography. 9(SOSI"): 0.54 (t, 4H), 1.38 (t, 1H), 2.58 (z, ЗН), 4.08 (a, 2H), 7.28 (a, 2H) , 7.57 (yes, 2H).

Preparatory example 59 5-Acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-nitropyridazin-3(2H)-one

The title compound (yield 3795) is obtained from the title compound of Preparative Example 58 according to the experimental procedure described in Preparative Example 31. 9(SOCI”): 0.46 (t, 2H), 0.62 (t , 2H), 1.45 (t, 1H), 2.21 (v, 3H), 4.18 (y, 2H), 7.21 (t, 2H), 7.45 (t, 2H).

Preparatory example 60

Ethyl ether of 5-methyl-4-(naphthalene-1-carbonyl)isoxazole-3-carboxylic acid Ge

The title compound is obtained as a solid (yield 9090) from (5) 1-naphthalen-1-yl-butan-1,3-dione IVapspene sei a); (Zal. Sit. Ma; 1940, m.70, p.134-40 according to the method described in preparatory example 2. 9(SOSI"): 0.8 (Y, ZN), 2.61 (in, ZN) , 3.81 (a, 2H), 7.40-8.61 (t, 7H).

Preparatory example 61 p

Z-Methyl-4-naphthalen-1-yl-bH-isoxazolo!|Z3,4-4|pyridazin-7-one so

The compound specified in the title is obtained as a solid (yield 50905) from the compound specified in the title of Preparative Example 60, according to the method described in Preparatory Example 7. And c) 9(SOCI"): 1.99 (c, ZN), 7.43-8.10 (t, 7H), 9.82 (in, 1H). them

Preparatory example 62

Zo 6-Ethyl-3-methyl-4-naphthalen-1-yl-6EN-isoxazoloi|Z,4-4|Ipyridazin-7-one v.

The title compound is obtained as a solid (yield 90905) from the compound indicated in the title of Preparative Example 61 by the method described in Preparative Example 17. 9(SOCIv): 1.46 (Y, ЗН), 1.97 ( c, ZN), 4.37 (a, 2H), 7.43-7.76 (t, 5H), 7.96-8.07 (t, 2H). "

Preparative example 63 5-Acetyl-4-amino-2-ethyl-6-(naphthalen-1-yl)upyridazin-3(2H)-one C c The title compound is obtained as a solid (yield 85905) from the compound, indicated in "from the title of preparatory example 62, according to the method described in preparatory example 23." , 7.44-8.00 (t, 7H).

Preparatory example 64 6-Ethyl-4-phenyl-1,6-dihydroisoxazolo|3,4-4|pyridazine-3,7-dione and To a stirred solution of PPA (354 g) in 354 ml of ethanol at 09, ethyl hydrazine oxalate -I (14 .58g, 97.09mmol) and the compound indicated in the title of Preparative Example 37 (5.9g, 97.09mmol). The resulting mixture is stirred at 402 overnight. Then let it cool to room temperature and carefully add water until a precipitate appears. Stir for 1 hour at 02C and then the target product (65) is collected by filtration and washed with ethanol (2.04g, yield 35905).

Kz 9(SOSIv): 1.44 (, ЗН), 4.30 (ad, 2Н), 7.42 (t, ЗН), 7.90 (t, 2Н).

Preparatory example 65 6-Ethyl-1-(3-fluorophenyl)-4-phenyl-1,6-dihydroisoxazolo!|3,4-4|pyridazine-3, 7-dione

A mixture of the compound indicated in the title of Preparative Example 64 (1.03g, 4mmol), 3-fluorophenylboronic acid (1.12g, 8.0mmol), anhydrous copper acetate (1.09g, b.Ommol), triethylamine (1.11ml, 8.Omol) and (F) activated molecular sieves (2.9g, 4A) in dry dichloromethane (HOml) are stirred in air at room temperature

GI temperature during the night. The reaction mixture is filtered through a layer of ZO" and eluted with dichloromethane.

The solvent was removed under reduced pressure to give the title compound (500 mg, yield 369). 9(SOSIv): 1.45 (Her, ZN), 4.32 (a, 2H), 7.12 (t, 1H), 7.42 (t, ZN), 7.52 (t, ZN), 7.85 (t, 2H).

Examples b5

The following abbreviations and conventions are used in the following tables:

Me methyl;

Meo methoxy;

E ethyl;

Isch Kv) ethoxy;

IRg isopropyl; 19 IPO isopropoxy;

MR g n-propyl;

Vp benzyl;

VpOo benzyloxy;

MVy n-butyl;

Pyridyl rouge;

RI phenyl; (3-Ac)Pp 3-acetylphenyl; (4-Ac)Pp 4-acetylphenyl; c (2-VORI 2-bromophenyl; o (3-VORI 3-bromophenyl; (4-VORI 4-bromophenyl; (2-SEZ)Pp 2-trifluoromethylphenyl; (3-SEZ)Py 3-trifluoromethylphenyl; se

Zo (2-SEZO)RY 2-trifluoromethoxyphenyl; co (4A-SEZO)RY 4-trifluoromethoxyphenyl; (4-SNHSOMN)RY / 4-acetamidophenyl; that) (2-C)ZRYi 2-chlorophenyl; che (3-C)ZRY Z-chlorophenyl; (4-C)ZRY 4-chlorophenyl; - (2-SYRU 2-cyanophenyl; (3-SYRU Z-cyanophenyl; (A-SYRU 4-cyanophenyl; « 20 (2-SOMNO)RY 2-carbamoylphenyl; z c (3-SOMNO)RY Z-carbamoylphenyl; c (4-SOMNOI)RY 4-carbamoylphenyl; and » (2-SOHRY 2-carboxyphenyl; (3-SOHRY Z-carboxyphenyl; (4-SOHRY 4-carboxyphenyl; - (4-COoMe)Pp 4-methoxycarbonylphenyl; -I ( 4-CO2BORES 4-ethoxycarbonylphenyl; sl (3-EU)RY 3-ethoxyphenyl; (2-DRY 2-fluorophenyl; (95) 50 (3-/)DRY 3-fluorophenyl;

From (4-DRY 4-fluorophenyl; (4-NOMSNI)RY 4-aminomethylphenyl; (2-HOSHOI)RY 2-hydroxymethylphenyl; (3-HOSHO)RY 3-hydroxymethylphenyl;

Gee! (4-NOSNO)RY 4-hydroxymethylphenyl; (2-Me)Pp 2-methylphenyl; where (3-Me)Pp 3-methylphenyl; (4-Me)Pp 4-methylphenyl; 60 (4-Meoyu)?P n 4-dimethylaminophenyl; (2-Meo)Pp 2-methoxyphenyl; (3-Meo)Ry 3-methoxyphenyl (4-Meo)Ry 4-methoxyphenyl; (3-Mez)Rpy 3-methylthiophenyl; bo (4-Mez)Pp 4-methylthiophenyl;

(4-Meb5ORI 4-methylsulfinylphenyl; (2-MO2)Rpy 2-nitrophenyl; (3-MO2)RY Z-nitrophenyl; (4-MO2)RY 4-nitrophenyl; (3-ONIRY Z-hydroxyphenyl; (4-RYURY 4-phenylphenyl; (4-RuddCHNo 4-pyridylmethyl; (2-502МНа)П 2-sulfamoylphenyl; (4-502МНа)РЙ 4-sulfamoylphenyl; (4-502МН(пВы)у)П i. 4-(М- n-butyl)sulfamoylphenyl; (3-8HRI 3-mercaptophenyl; (44VSHRI 4-tert-butylphenyl.

TIN and bshtdie and and . her | NO 1 Beat her! s yn she sce Z p: NI SHO ssh shiny nin Z B shin nyny en Y Ge y: a en ese navy ny o zabzh yam toku day pet r

SD sho S z v v y m

Ge shi OO ko ONE. ON ZMO ze SHE NN SHE 5 shchi i shi t

And (S oodshte oddasho ZM to Y shlyu s | yasyr la nt 7 ekol medyuya What DV and act. ny yazh tex Kk i stamens lie zh ! and - this. She about ЦИ burn Y drink ! y And what: se zhdy o t 4

And they don't know: a veteran is a veteran

Co) | I. and SHY E!

Her. :Erptk Kk pdrya pIa kose so dddnl-etutya ha tvvelchik o syn NOT M shh healed -y

She: y pn ke NN ko dv POV oz EN pah Mehlttnnnyah 60 b5 s y she sikh s NN NN y s s s s s s s s s s s s s

Shk and re WRYANIAMYA in "hai Tr."

SHY y p in pn pi I shi shi SHY SHYNS MO

I om Uh p HO Chon, KO sm ide ii -:33 pe i B y dey THIS 4 shi shen she SHY: VYSH - in other not yet r « zo KESH SHYNY SHY shi SHY ME v) s z -I -I ( 9) at 50

What) (F; ko 60 65 t Be sh Ka koda t field te

Te and dya IY zn still And I shk x 9 to and 1 and And to her eat shi still because Go I:

I Y 4 she: in E her grain of doryit, LLYUY KA ŽytTRt Y VEOH XX nka still sht TYA HORI EMPTKya, "B pi TEM PI ILYUVU u. yayanto tv

I sh-o tires we and TIRES TIDYOMI urn ns; tires re xx: podo On ry sch d) І и в . ! ssh shi seh seh seh seh сч ж шк жи и а аби ю и ШИ ШИН хх NN I YN I SHK: s prasch shi shi sha -I -I 1 o 50 to)

F) why 65

Oh shi shi M m young still and. Shit! : What's wrong with them Ge; i shi k i ! And some I Y. I penya PKEE rya with 2 tires shi shishshishchi shizhshn y sh y y ! | : o What else is going on

With still shchi ne en SHE: he NN IN CURRENTS, y shi shi shi SHE S sh, with WHAT still shi shshNyu I m shi ny shi ya she. "shi sha tnodh sht shlyu tet - z -I -I 1 s) 70 what) (F) ko 60 65 tsi K- | o I ii y : and pozhh EY y

Ge and pglzh pyu: today chen td ven eteya zdo pouf pryona oh still in SHE: i se la tlia z dhshlya noya No, sho tyh "o harm pemya i. ne - so -I -I 1 s) 70 that) (F) ko 60 65 in their Yanina kove, loy and siv t UT shcha. ;

ME KU E Ten; Sonya Zhiron: ny Ne nn: DYN i YN

That g | what's up with ? o o kn still po My iga Y so i 0 shashi shcha shi shchi « pnia DE I sel ped KKD vn s KO Zhde EE IV ZA -I -I u o 50 z (F. t bo b5 shchi shiny shen: shi: DY shen r NN NN ii zhi shishshe shi shi shi She NN zh, peaks MN SHHY s SHK 1 zo still ysh shi i SHY SHYN SHY so i shi nn Shi NN MELON iz- z5 SHI; t i g Y -

Z OV GY NI Ki sh Pet: and MORE! ! « with Z and her. ey sh I r -I -I 2 o 50 then

F) o) because b5

12 E Ge shk; Kt i Y I. st - ! What is that?

I i G dr i Y pa chsh i Ku t p

Ge si g her Pn You? Хо их І с ШХЯе Z че рах і -I -I 1 s) 0

Co.)

F) name) in b5 ze some of them from AI | | gli and | s shi Ge | ! and with -I -I 1 s 50

Co.)

F) name) 60 b5

SHE. Shi SHE not -

PE s ss she they m m y 7 I m mn she sh- what pl what - -I -I 1 syu 70 what)

F) ko 60 65 syh oh me Kesh Tl" be E pen sho yiv ryng ha "OK i Y I | ! / she . I S SCHI nty ky V i nn m o i p p p v M V PZ p ia I shiny shi i Her" Es (5 ! sh dr a i | -k y ne ve ! o

Pe I ho and still pk i | What is it? i ch zo ShK I "y i p. pi, | but » vdE you CHIK VM. бжуй 0 ET BE Тич ЖЕ УТИ ня LOOTL. и ТЛИ Тео MAY шту St ши -I -I 1 o 50 what) (F) ko bo b5 і і 1 vfeetueya і і mn nii I BO і: 7 sh! | shi ; no z shin nyny nor yet INN KN and p sho i ge Be y: SCHI poi KE : . E Mt, N E i

And VE | in p pe By I y x y prstvor: y syak Uzh To with y pre spek puu pi» pek oh y p cha y Ha " more: ih pyaAt pe her і o as o |ta Pod ta: with SHON NE ke shko in what and І 5 | | ;

I | | Т МН | : ес в нн пн ей и ше не вн » Я шш вх | vyya i and ; "She / go | : : -I -I 1 oz 7 do) (F. ko 60 65 she ; Shk : і I et ku scho "a stva a GE і t і oi ko i n be ley yam y LEK p Eintt her "name

And | What's the point of this pul poh y : S / y shiny shi PO dit Visn

I en I I stump and !

NECK! i shchi shi | it's k..

Oh no | She ha pi i) tires | with. th r" 5 "th Kudi MK pmeya V i s

She: shchi pi yi!

E Y T HER "E E her every day!" ; ! oh

Bktsianya This. I SA v sho Z yi nya PU KE I yuyu shiya pn pi And ate it; ep I o ; - : i. B i, ; pryu I Hm cha sv! and sashe ge | house villa Ek! from AI: in more | l i - y o ve at z I Cohen certain I ptednnnnne eh ter still vZ Ten" which Jan--I

Ban Bred is I ZE: Z: y -I HER B nya nt I Y | KU r y AEN term verk TI ev SYA I TE re YAKE KN gy ME s v | and: on Day and | ! g and I g. E Zhe i and I

B. nkh women) dream thorns Mne skh, sehshezhet "BosKYUZheyanh soyu seshivnyah shomafFehs sehlyust sasherenerryunya sny fo I and ni tanya ono aa se yy nashe chen she sk syaaya eyeny NM sei M ns sotki z vv sht: WE M HIGHER ren Te TE 7 av KE EVet yah sa 7" elshanyu o bovvenvni o Bornnia Von vav

SAWA I KEN MATEYA TEN KANWI BACH TSO ANN THEZ NED KENE:

The symbol X refers to only one attachment point. It does not represent any atom.

Example 1 5-Acetyl-2-ethyl-4-((3-fluorophenyl)amino|-6-phenylpyridazin-3(2H)-one b5 y . y ,

A mixture of the compound indicated in the title of Preparative Example 22 (250mg, 0.97mmol), 3-fluorophenylboronic acid (272mg, 1.94mmol), anhydrous copper acetate (265mg, 1.4bmmol), triethylamine (0.27ml, 1.94mmol) and activated molecular sieves (720mg, 4A) in dry dichloromethane (12ml) are stirred in air at room temperature for 24 hours. The reaction mixture is filtered and the solvent is removed under reduced pressure.

The resulting residue was purified by express column chromatography (5105, dichloromethane-ethyl acetate), thereby obtaining the title compound (216 mg, yield 6390).

T.pl. 176.5-178.296. 9(SOSI"): 1.45 (Her, ZN), 1.74 (v, ZN), 4.30 (a, 2H), 6.76 (t, 1H), 6.85 (t, 2H) , 7.25 (t, 1H), 7.40 (t, 5H), 8.24 (v, 1H).

Example 2 5-Acetyl-4-Y(3,5-difluorophenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one

The title compound was prepared as a solid (yield 54905) from the title compound of Preparative Example 22 and 3,5-difluorophenylboronic acid by the method described in Example 1.

T.pl. 243.4-244.626. 9(SOSIv): 1.44 (I, ЗН), 1.80 (в, ЗН), 4.31 (а, 2Н), 6.59 (t, ЗН), 7.40 (t, 5Н), 8.26 (in, 1H).

Example C 5-Acetyl-4-H(3,5-dichlorophenyl)amino|-2-ethyl-b-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid (yield 55905) from the title compound of Preparative Example 22 and 3,5-dichlorophenylboronic acid by the method described in Example 1.

T.pl. 254.4-254.626. 9DMSO-a in): 1.33 (Y, ЗН), 1.84 (з, ЗН), 4.17 (d, 2Н), 7.1 (в, 1Н), 7.19 (t, 2Н) , 7.38 (t, 5H), 9.14 (in, 1H).

Example 4 5-Acetyl-2-ethyl-4-((3-nitrophenyl)amino)|-b-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid (yield 40905) from the title compound of Preparative Example 22 and 3-nitrophenylboronic acid by the method described in Example 1. c

T.pl. 241.8-243.726. o 9(SOSI"): 1.45 (I, ЗН), 1.78 (в, ЗН), 4.31 (а, 2Н), 7.45 (t, 7Н), 7.84 (в, 1Н ), 8.02 (y, 1H), 8.73 (v, 1H).

Example 5 5-Acetyl-2-ethyl-4-((4-methylphenyl)amino|-6-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid (yield 50905) from the compound indicated in the title of Preparative Example 22 and 4-methylphenylboronic acid according to the method described in Example 1.

Mass spectrum (I EM): t/7 347 (M--1)7. 9(SOSIv): 1.46 (i, ЗН), 1.58 (5, ЗН), 2.34 (8, ЗН), 4.31 (а, 2Н), 6.95 (й, 2Н), 7.13 (d, 2H), 7.34 (t, 5H), 8.03 (c, 1H). and

Example 6-5-Acetyl-2-ethyl-4-((2-methylphenyl)amino|-6-phenylpyridazin-3(2H)-one m

The title compound was prepared as a solid (yield 54905) from the title compound of Preparative Example 22 and 2-methylphenylboronic acid by the method described in Example 1.

T.pl. 189.8-190.726. 9(SOSIz): 1.46 (Her, ZN), 1.51 (in, ZN), 2.33 (in, ZN), 4.31 (a, 2H), 6.97 (d, 1), 7.11 (t, 2H), 7.23 (t, « 20 1H), 7.34 (t, 5H), 7.81 (v, 1H). - c Example 7 5-Acetyl-2-ethyl-4-((2-methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one from The title compound is obtained as a solid (yield 30905) from the compound, specified in the title of preparatory example 22, and 2-methoxyphenylboronic acid according to the method described in example 1.

T.pl. 205.4-206.826. -i Z(DMSO-yv): 1.33 (i, ZN), 1.52 (85, ZN), 3.73 (8, ZN), 4.16 (a, 2H), 6.85 (Ii , 1H), 6.97 (ad, 1), 7.02 (a, 1H), 7.14 (6 1H), 7.26 (t, 2H), 7.36 (t, ЗН), 8, 47 (c, 1H). 7 Example 8 sl 5-Acetyl-2-ethyl-4-(1-naphthylamino)-6-phenylpyridazin-3(2H)-one

The compound specified in the title is obtained as a solid (yield 51905) from the compound specified in the title of Preparative Example 22 and 1-naphthylboronic acid according to the method described in Example 1. with T.pl. 196.8-197.726. 9SOCIz): 1.23 (8, ZN), 1.52 (ZN), 4.36 (4, 2H), 6.85 (5 1), 7.34 (t, 6H), 7.58 (t , 2H), 7.75 (a, 1H), 7.86 (4, 1H), 8.12 (da, 1H), 8.27 (8, 1H).

Examples 9-20 5-Acetyl-2-ethyl-4-C4-(methylthio)phenyl|amino)-6-phenylpyridazin-3(2H)-one o 5-Acetyl-4-((4-acetylphenyl)amino|- 2-ethyl-b-phenylpyridazin-3(2H)-one im) 5-Acetyl-4-(4-«(dimethylamino)phenyl|amino)-2-ethyl-6-phenylpyridazin-3(2H)-one 5- Acetyl-2-ethyl-4-(2-naphthylamino)-6-phenylpyridazin-3(2H)-one 60 5-Acetyl-4-((2-chlorophenyl)amino|-2-ethyl-b-phenylpyridazin-3( 2H)-one 5-Acetyl-2-ethyl-6-phenyl-4-(3-trifluoromethoxy)phenyl|amino)pyridazin-3(2H)-one 5-Acetyl-2-ethoxy-6-phenyl-4- ((2--(trifluoromethyl)phenyl|amino)pyridazin-3(2H)-one 5-Acetyl-2-ethyl-4-((2,5-dimethoxyphenyl)amino|-6-phenylpyridazin-3(2H)- one 5-Acetyl-2-ethyl-4-|(2-fluoro-3-methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one 65 5-Acetyl-4-((2,3-dichlorophenyl)amino |-2-ethyl-b-phenylpyridazin-3(2H)-one 5-Acetyl-4-|(5-chloro-2-methoxyphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one

5-Acetyl-2-ethyl-4-|(5-fluoro-2-methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one

The compounds indicated in the title are synthesized from the compound indicated in the title of Preparative Example 22 and the corresponding boronic acid according to the method described in Example 1. EBI/M5 data (mass spectroscopy with electrospray ionization) and retention time according to РХВР data are shown in Table 3. 81 vyu01v3 o fri v11v6 nEti ni MON iv 6 Jan01vya yuyu 1vv July | for | in

Example 21

4-(15-acetyl-2-ethyl-6-14-(methylthio)phenyl|-3-oxo-2,3-dihydropyridazin-4-yl)iamino)benzoic acid methyl ester

The title compound is obtained as a solid (yield 20905) from the title compound of Preparative Example 23 and 4-(methoxycarbonyl)renylboronic acid by the method described in Example 1.

Mass spectrum (I EM5)): t/7 438 (М.А1)7.

Holding time: 9.4 min. He 9SOSIz): 1.42 (B ЗН), 1.81 (в, ЗН), 2.46 (в, ЗН), 3.92 (в, ЗН), 4.32 (а, 2Н), 7, 05 (a, 2H), 7.23 (t, so

AN), 7.99 (y, 2H), 8.38 (8, 1H).

Examples 22-24 Io) 5-Acetyl-2-ethyl-4-((3-fluorophenyl)amino|-6-(4-(methylthio)phenyl|pyridazin-3(2H)-one m 4-(15-Acetyl -2-ethyl-6-I4-(methylthio)phenyl|-3-oxo-2,3-dihydropyridazin-4-ilyamino)benzoic acid 5-Acetyl-2-ethyl-6-(4-(methylthio)phenyl|- 4-(1-naphthylamino)pyridazin-3(2H)-one -

The compounds indicated in the title are synthesized from the compound indicated in the title of Preparative Example 23 and the corresponding boronic acid according to the method described in Example 1. EBI/M5 data (mass spectroscopy with electrospray ionization) and retention time according to РХВР data are given in Table 4. "from the village g" - | Example 25 5-Butyryl-2-ethyl-4-((3-fluorophenyl)amino)|-6-(4-(methylthio)phenyl|-pyridazin-3(2H)-one The title compound is obtained from the compound, specified in the title of preparatory example 24, and with 3-fluorophenylboronic acid according to the method described in example 1. syu 50 Mass spectrum (IEM): t/7 426 (MaА1)"

Holding time: 10.2 min.

III Example 26 2-Ethyl-5-(2-ethylbutanoyl)-4-((3-fluorophenyl)amino1|-6-(4-(methylthio)-phenyl|Ipyridazin-3(2H)-one

The compound indicated in the title is obtained from the compound indicated in the title of preparatory example 25 and 5B 3-fluorophenylboronic acid according to the method described in example 1. o Mass spectrum (I EM5): t/72 454 (MA1)"

Holding time: 11, 1 min. Example 27 2-Ethyl-5-(2-ethylbutanoyl)-6-(4-(methylthio)phenyl/|-4-(naphth-1-ylamino)pyridazin-3(2H)-one 60 The title compound is obtained from the compound specified in the title of Preparative Example 25 and 1-naphthylboronic acid according to the method described in Example 1.

Mass spectrum (I EM5): t/7 486 (M--1)"

Holding time: 10.8 min.

Example 28 65 Methyl ether of 4-((5-acetyl-2-ethyl-6-(4-(methylsulfinyl)phenyl|-3-oxo-2,3-dihydropyridazine-4-ilyamino)benzoic acid

The title compound is prepared as a solid (2095) from the title compound of Preparative Example 26 and 4-(methoxycarbonyl)phenylboronic acid by the method described in Example 1.

Mass spectrum (KM): t/2 454 (MAT) Kk.

Holding time: 7.2 min. 9SOSIz): 1.42 (B ЗН), 1.81 (в, ЗН), 2.78 (в, ЗН), 3.93 (в, ЗН), 4.32 (а, 2Н), 7.10 (a, 2H), 7.58 (a, 2H), 7.75 (9, 2H), 8.01 (a, 2H), 8.35 (c, 1H).

Examples 29-35 5-Acetyl-2-ethyl-4-((3-fluorophenyl)amino|-6-(4-(methylsulfinyl)-phenyl|pyridazin-3(2H)-one 70 5-Acetyl-4-( (3-chlorophenyl)amino|-2-ethyl-6-I(4--methylsulfinyl)-phenyl|pyridazin-Z3(2H)-one 5-Acetyl-2-ethyl-4-((2-methylphenyl)amino1| -6-(4--(methylsulfinyl)-phenyl|pyridazin-Z3(2H)-one 5-Acetyl-2-ethyl-6-(4-(methylsulfinyl)phenyl|-4-(1-naphthylamino)-pyridazin- 3(2H)-one 5-Acetyl-2-ethyl-6-(4-(methylsulfinyl)phenyl|-4-(3-nitrophenyl)-amino|Ipyridazin-3(2H)-one 5-Acetyl-2-ethyl -6-I(4-(methylsulfinyl)phenyl|-4-(2-methoxyphenyl)-amino|pyridazin-3(2H)-one 5-Acetyl-2-ethyl-6-(4-(methylsulfinyl)phenyl|- 4-(3-Methoxyphenyl)amino|pyridazine-3(2H)-one

The compounds indicated in the title are synthesized from the compound indicated in the title of Preparative Example 26 and the corresponding boronic acid according to the method described in Example 1. EBI/M5 data (mass spectroscopy with electrospray ionization) and retention time according to РХВР data are shown in Table 5. yu sch o s

Example 36 5-Acetyl-6-3-(cyclopentyloxy)-4-methoxyphenyl|-2-ethyl-4-((3-fluorophenyl)amino|pyridazin-3(2H)-one She

The title compound is prepared from the title compound of Preparative Example 27, and (a

of 3-fluorophenylboronic acid according to the method described in example 1.

Mass spectrum (I EM5): t/72 466 (Ma-1)" t

Holding time: 10.3 minutes. what

Example 37 5-Acetyl-6-3-cyclopentyloxy)-4-methoxyphenyl|-2-ethyl-4-(1-naphthylamino)pyridazin-3(2H)-one

The title compound is obtained from the title compound of Preparative Example 27 and 1-naphthylboronic acid according to the method described in Example 1.

Mass spectrum (I EM5): t/72 498 (MaА1)" - s Retention time: 10.8 min. and Examples 38-40 "" 5-Acetyl-2-methyl-4-(1-naphthylamino)-6- phenylpyridazin-3(2H)-one 5-Acetyl-4-I(3,5-difluorophenyl)amino|-2-methyl-b-phenylpyridazin-3(2H)-one 5-Acetyl-4-((3-chlorophenyl )amino|-2-methyl-6-phenylpyridazin-3(2H)-one -I The compounds indicated in the title are synthesized from 5-acetyl-4-amino-2-methyl-6-phenylpyridazin-3(2H)-one |Oai ! Ria?g,

M., Sisiapi, S, Siomappopi, M.R., Negyegosusiev, 1991, m.32, p.1173-9) and the corresponding boronic acid for this. by the method described in example 1. The data of EBI/M5 (mass spectroscopy with electrospray ionization) and retention time "sl according to the data of РХВР are shown in Table 6.

Fo

From vv syu 1lv011vo (F. Examples 41-43 ko 5-Acetyl-2-benzyl-4-((3,5-difluorophenyl)amino|-6-phenylpyridazin-3(2H)-one 5-Acetyl-2-benzyl -4-|((Z-fluorophenyl)amino|-6-phenylpyridazin-3(2H)-one in 5-Acetyl-2-benzyl-4-|((Z-chlorophenyl)amino|-6-phenylpyridazin-Z3( 2H)-on

The compounds indicated in the heading are synthesized from the compound indicated in the heading of Preparative Example 28 and the corresponding boronic acid according to the method described in Example 1. EBI/M5 data (mass spectroscopy with electrospray ionization) and retention time according to РХВР data are shown in Table 7. 65 Example |EVI/M5 t/e (M.N) Retention time (min.)

in

Examples 44-46 5-Acetyl-2-(cyclopropylmethyl)-4-(1-naphthylamino)-6-phenylpyridazin-Z3(2H)-one 5-Acetyl-2-(cyclopropylmethyl)-4-((3-fluorophenyl) amino)|-b-phenylpyridazin-Z3(2H)-one 5-Acetyl-4-((Z-chlorophenyl)amino|-2-(cyclopropylmethyl)-6-phenylpyridazin-3(2H)-one 70 Compounds indicated in the title is synthesized from the compound indicated in the title of Preparative Example 29 and the corresponding boronic acid according to the method described in Example 1. EBI/M5 data (mass spectroscopy with electrospray ionization) and retention time according to РХВР data are given in Table 8. and in »yu011711v8

Example 47 20 5-Acetyl-4-(1-naphthylamino)-6-phenyl-2-pyridin-4-ylmethylpyridazin-3(2H)-one

The compound indicated in the title is obtained from the compound indicated in the title of Preparative Example 30 and 1-naphthylboronic acid according to the method described in Example 1.

Mass spectrum (IM): t/7 447 (МА1)"

Holding time: 8 hours. 29 Example 48 Ge) 5-Acetyl-4-((3-fluorophenyl)amino|-6-phenyl-2-pyridin-4-ylmethylpyridazin-3(2H)-one

The title compound is prepared from the title compound of Preparative Example 30, and

of 3-fluorophenylboronic acid according to the method described in example 1. ch 30 Mass spectrum (I EM5): t/72 415 (МА1)"

Holding time: 7.8 min. co

Example 49 5-Acetyl-2-ethyl-4-((3-methylphenyl)amino|-6-phenylpyridazin-3(2H)-one o

Add 57 mg (0.20 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one to the stirred solution. Rial, Yitch

M ei aii,, 9. May. Spent 1997, m. 40, r. 1417| (57mg, O0.20mmol) in ethanol (2ml) add m-toluidine 35 (b4img, 0.b6bmmol) in portions. The resulting mixture is stirred at room temperature for ЗОхв. and then the formed product is collected by filtration, washed with ethanol and diethyl ether, thereby obtaining the title compound (24 mg, yield 3590).

Mass spectrum (KM): t/2 348 (MA) Kk. "

Holding time: 9,Ochv. - about 9SOSIz): 1.42 (6 ЗН), 1.57 (в, ЗН), 2.50 (в, ЗН), 4.30 (а, 2Н), 6.87 (t, 2Н), 7.03 (a, 18), 7.17 (a, c 1H), 7.48 (t, 5H), 8.03 (c, 1H). Example 50 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzoic acid

The title compound is obtained as a solid Kk! -1 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Mei aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417 )| and 4-aminobenzoic acid according to the method described in example 49. The obtained product is recrystallized from a mixture of ethanol/dichloromethane (yield 76905). sl T.pl. 273.0-273.496. 5 (DMSO-yv): 1.32 (Ii, ЗН), 1.83 (в, ЗН), 4.17 (а, 2Н), 7.04 (9, 2Н), 7.31 (t, 2Н ), 7.40 (t, ЗН), 7.76 and (9, 2Н), 9.20 (in, 1Н), 12.72 (rev, 1Н).

GI Example 51 2-K5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|Ibenzoic acid

The title compound is obtained (yield 25905) from 5-acetyl-2-ethyl-4-nitro-b6-phenylpyridazin-3(2H)-one (Rai! Ria;, Meiai., U. Mei. Spet. 1997 , m.40, p.1417) and 2-aminobenzoic acid according to the method described in example 49. iF) Mass spectrum (I EM5): t/7 348 (М--1)7. ko 9 (SOSIz): 1.42 (B ЗН), 1.83 (в, ЗН), 4.18 (ad, 2Н), 6.82 (а, 1), 7.07 (и, тн), 7.42 (t, 6H), 8.02 (a, 1H), 10.02 (c, 1H), 12.72 (rv, 1H). 60 Example 52 5-Acetyl-4-((3-chlorophenyl)amino|-2-ethyl-b-phenylpyridazin-3(2H)-one

The title compound is obtained (yield 64965) from 5-acetyl-2-ethyl-4-nitro-b6-phenylpyridazin-3(2H)-one (Rai Riag, M ega!., 9. Med. Spet. 1997, m .40, p.1417| and 3-chloroaniline according to the method described in example 49.

T.pl. 189.0-190.626. 65 Z(DMSO-yv): 1.34 (His ZN), 1.75 (8, ZN), 4.18 (a, 2H), 7.02 (t, 1H), 7.17 (t, 2H ), 7.30 (t, ZN), 7.40 (t,

ЗН), 9.05 (in, 1Н).

Example 53 5-Acetyl-4-((3Z-bromophenyl)amino|-2-ethyl-b-phenylpyridazin-3(2H)-one

The title compound is obtained (yield 6595) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Rai Riag, Meyi ai., U. Med. Spet. 1997, m .40, p.14171| and 3-bromoaniline according to the method described in example 49.

T.pl. 191.3-192.02С

Z(DMSO-yv): 1.33 (ZN), 1.75 (8, ZN), 4.17 (а, 2Н), 7.03 (t, 1Н), 7.22 (t, ZN), 7.30 (t, 2H), 7.42 (t,

ЗН), 9.06 (in, 1Н).

Example 54 5-Acetyl-4-Y(3,4-dimethoxyphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one

The title compound is obtained (yield 7695) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Rai Riag, Moscow, 9. Med. Spet. 1997, Moscow. 40, p.1417| and 3,4-dimethoxyaniline according to the method described in example 49.

Mass spectrum (I EM5): t/7 388 (Ma-1)" 9(SOSI"): 1.42 (i, ZN), 1.65 (8, ZN), 3.78 (t, 6H) , 4.25 (a, 2H), 6.62 (t, 2H), 6.78 (t, 1H), 7.38 (t, 5H), 7.98 (c, 1H).

Example 55 5-Acetyl-2-ethyl-4-C4-(hydroxymethyl)phenyl|amino)-6-phenylpyridazin-3(2H)-one

The title compound is obtained (yield 2095) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Sa! Ri7, Mey aY.,, U. Med. Spect. 1997 , m.40, p.1417) and (4-aminophenyl)methanol according to the method described in example 49.

Mass spectrum (I EM5): t/7 388 (Ma-1)" 9(SOSI"): 1.62 (i, ZN), 1.84 (v, ZN), 2.10 (B5, 1H) , 4.25 (a, 2H), 4.63 (5, 2H), 7.05 (a, 2H), 7.38 (t, 7H), 8.22 (c, 1H).

Example 56 5-Acetyl-4-(1,1-biphenyl-4-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one

The title compound is obtained (yield 22905) from 5-acetyl-2-ethyl-4-nitro-b6-phenylpyridazin-Z3(2H)-one SI (|Vai Riag, Mei ai., U. Med. Spet. 1997 , m.40, p.1417) and 1,1"-biphenyl-4-amine according to the method described in example 49. (5)

Mass spectrum (I EM5): t/72 410 (M-1)" 9(SOSI"): 1.42 (i, ЗН), 1.77 (v, ЗН), 4.28 (а, 2Н) , 7.15 (a, 2H), 7.38 (t, 9H), 7.56 (t, ЗН), 8.22 (8, 1H).

Example 57 5-Acetyl-2-ethyl-b-phenyl-4-(5,6,7,8-tetrahydronaphthalene-1-ylamino)pyridazin-3(2H)-one c

The title compound was obtained (yield 2395) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one with

Ioah! Ria;, M ei aiYi.,, U. Med. Spent 1997, m. 40, r. 1417| and 5,6,7,8-tetrahydronaphthalene-1-amine according to the method described in example 49. Io)

Mass spectrum (KM): t/2 388 (M'-1) ich- 9SOSIz): 1.42 (B ZN), 1.44 (5, ZN), 1.78 (t, 4H), 2, 67 (t, 4H), 428 (a, 2H), 6.75 (t, 1H), 6.98 (t, 2H), 7.36 (t, 5H), 7.78 (c, 1H). -

Example 58 5-Acetyl-4-|3-(cyclopentyloxy)-4-methoxyphenyl|amino)-2-ethyl-b6-phenylpyridazin-3(2H)-one

The title compound is obtained (yield 2395) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one "

Ioah! Ria;, M ei aiYi.,, 9. May. Spent 1997, m. 40, p. 1417) and 3-(cyclopentyloxy)-4-methoxyaniline (International patent application UUCHO 9325517) according to the method described in example 49. o, c Mass spectrum (I EM5): t/72 448 (MA1)" "» 9(SOSIz): 1.45 (t, TON), 1.90 (t, 4H), 3.82 (v, ЗН), 4.32 (a, 2H), 4.70 (t, 1H), 6.66 (t, ZH), 7.38 (t, " BN), 7.82 (v, 1H).

Example 59 5-Acetyl-2-ethyl-4-N-methyl-N-phenylamino|-b-phenylpyridazin-3(2H)-one ce. The title compound is obtained (yield 2895) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Rai Riag, Mega!., 9. Med. Spet. 1997 , m. 40, r. 1417)| and M-methylaniline according to the method described in example 49.

Mass spectrum (I EM5): t/72 348 (MaА1)" at 9(SOSI"): 1.42 (, ZN), 1.83 (5, ZN), 3.28 (8, ZN), 4 .32 (a, 2H), 6.78 (t, 2H), 6.90 (t, 1H), 7.25 (t, 1H), 7.42 (t, 6H). so 20 Examples 60-85 5-Acetyl-4-(1,3-benzodioxol-5-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one from 5-Acetyl-2-ethyl-4-(4-methoxyphenyl)amino| -6-phenylpyridazin-3(2H)-one 5-Acetyl-4-((4-chlorophenyl)amino|-2-ethyl-b-phenylpyridazin-3(2H)-one 5-Acetyl-4-(4-bromophenyl )amino|-2-ethyl-b-phenylpyridazin-3(2H)-one 29 5-Acetyl-2-ethyl-b6-phenyl-4-I3--trifluoromethyl)phenyl|amino)pyridazin-3(2H)-one

HF) 5-Acetyl-4-|(3-chloro-4-methoxyphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one 5-Acetyl-2-ethyl-4-((Z- hydroxyphenyl)amino|-6-phenylpyridazin-3(2H)-one 3-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzoic acid 5- Acetyl-2-ethyl-4-((2-fluorophenyl)amino|-6-phenylpyridazin-3(2H)-one 60 Ethyl ether 4-(5-acetyl-2-ethyl-3-oxo-6-phenyl-2 ,3-dihydro-pyridazin-4-ylamino)benzoic acid 5-Acetyl-2-ethyl-4-((4-fluorophenyl)amino|-6-phenylpyridazin-3(2H)-one 2-K5-acetyl-2- ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)iamino|-4-fluorobenzoic acid 3-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3- dihydropyridazin-4-yl)amino|benzonitrile 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-2-hydroxybenzoic acid bo 5-Acetyl- 2-ethyl-4-((3-hydroxy-4-methoxyphenyl)amino|-b6-phenylpyridazin-3(2H)-one

4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzamide 5-Acetyl-2-ethyl-4-yl3-(methylthio)phenyl|amino )-6-phenylpyridazin-3(2H)-one 5-Acetyl-2-ethyl-4-((3-methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one 5-Acetyl-4-((Z -acetylphenyl)amino|-2-ethyl-b-phenylpyridazin-3(2H)-one

T1A-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|renylacetic acid 5-Acetyl-4-I4-(tert-butylphenyl)amino|-2 -ethyl-6-phenylpyridazin-3(2H)-one 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzenesulfonamide 4-(A- 1(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|phenyl)-4-oxobutanoic acid 70 3-(5-Acetyl-2-ethyl-3 -oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-N-butylbenzenesulfonamide 5-Acetyl-2-ethyl-4-((1-oxo-2,3-dihydro-1H-inden-5 -yl)amino|-6-phenylpyridazin-3(2H)-one

M-14-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)lamino|phenyl)acetamide

The compounds indicated in the title are synthesized from 5-acetyl-2-ethyl-4-nitro-b6-phenylpyridazin-3(2H)-one. Riaye, M. ei aiI,, U. May. Spent 1997, m.40, p.1417) and the corresponding aniline according to the method described in example 49. The data of 7/5 ЕЗИ/М5 (mass spectroscopy with electrospray ionization) and the retention time according to РХВР data are given in table 9. бю | yav010v6 2 already 186 vv 1zo1vo y. вв 1вю щи вв вве ве 1193 сч зо о юм мм п 1 1вв в 1 1вю "shi tepto - s sviam 1vyu:" - Example 86 -I 4-(5-Acetyl-6-(3-chlorophenyl)- 2-ethyl-3-oxo-2,3-dihydropyridazine-4-ylamino|benzoic acid

The title compound is obtained (yield 3590) Kk) 1 5-acetyl-2-ethyl-4-nitro-6-(3-chlorophenyl)pyridazin-3(2H)-one |Oa! Ria7, M ei aiYi,, 9. May. Spent 1997, age 40, so 20 year 1417)| and 4-aminobenzoic acid according to the method described in example 49.

T.pl. 207.0-207.9 iz 9(SOSI"): 1.46 (i, ZN), 1.85 (5, ZN), 4.31 (a, 2H), 7.10 (a, 2H), 7.23 (t, 2H), 7.40 (t, 2H), 8.04 (a, 2H), 8.48 (5, 1H).

Example 87 5-Acetyl-6-(3-chlorophenyl)-4-(3-chlorophenyl)amino|-2-ethylpyridazin-3(2H)-one

The title compound is obtained from 5-acetyl-2-ethyl-4-nitro-6-(3-chlorophenyl)pyridazin-3(2H)-one |Oai

GF) Riag, M. ai., U. Med. Spent 1997, p. 40, p. 1417) and 3-chloroaniline according to the method described in example 49. yuyu Mass spectrum (I EM5): t/72 403 (Ma-1)"

Holding time: 10,Ochv.

Example 88 60 5-Acetyl-6-(33-chlorophenyl)-2-ethyl-4-((3-fluorophenyl)amino|pyridazin-3(2H)-one

The title compound is obtained from 5-acetyl-2-ethyl-4-nitro-6-(3-chlorophenyl)pyridazin-3(2H)-one |Oai

Riag, M. ai., U. Med. Spent 1997, p. 40, p. 1417) and 3-fluoroaniline according to the method described in example 49.

Mass spectrum (IEM): t/7 386 (M--1)"

Holding time: 9 hours. because Example 89

5-Acetyl-4-((3-chlorophenyl)amino|-2-ethyl-6-(4-fluorophenyl)pyridazin-3(2H)-one

The title compound is obtained (yield 7190) from the title compound of the preparative example

C1, and C-chloroaniline according to the method described in example 49.

T.pl. 190.9-191.4 9(SOSI"): 1.45 (Her, ЗН), 1.75 (в, ЗН), 4.29 (а, 2Н), 6.97 (а, 1Н), 7 .01 (t, 4H), 7.26 (t, 1H), 7.36 (t, 2H), 8.17 (v, 1H).

Example 90 5-Acetyl-4-((3Z-bromophenyl)amino|-2-ethyl-6-(3Z-fluorophenyl)pyridazin-3(2H)-one

The title compound is prepared (8595) from the title compound of Preparative Example 32 and 70 C-bromoaniline by the method described in Example 49.

T.pl. 169.0-170.7 9(SOSI"): 1.45 (i, ЗН), 1.77 (в, ЗН), 4.29 (а, 2Н), 7.01-7.38 (t, 8H), 8.22 (5.1H).

Example 91 5-acetyl-2-ethyl-4-(3-fluorophenyl)amino|-6-(3-fluorophenyl)pyridazin-3(2H)-one

The title compound is prepared (yield 8490) from the title compound of Preparative Example 32 and 3-fluoroaniline by the method described in Example 49.

T.pl. 173.5-174.6 9(SOCI3): 1.45 (, ЗН), 1.78 (в, ЗН), 4.30 (а, 2Н), 6.78 (t, 1Н), 6.89 (t, 2H), 7.11 (t, ЗН), 7.27 (t, 1H), 7.38 (t, 1H), 8.21 (8, 1H).

Example 92 5-Acetyl-4-((3-chlorophenyl)amino|-2-ethyl-6-(3-fluorophenyl)pyridazin-3(2H)-one

The title compound is prepared from the title compound of Preparative Example 32, and

Z-chloroaniline according to the method described in example 49.

Mass spectrum (I EM5): t/7 386 (M--1)" p

Holding time: 9.5 minutes. at

Example 93 5-Acetyl-4-((3-chlorophenyl)amino|-2-ethyl-6-(3-nitrophenyl)pyridazin-3(2H)-one

The title compound is obtained (yield 83906) Kk) 5-acetyl-2-ethyl-4-nitro-6-(3-nitrophenyl)pyridazin-3(2H)-one |Oa! Rial, May 9. Spent 1997, M.40,. DC ZES r. 1417| and 3-chloroaniline according to the method described in example 49.

T.pl. 173.0-174.296С at 5(СОСИ3): 1.46 (B ЗН), 1.81 (в, ЗН), 4.31 (ad, 2Н), 6.99 (а, 1Н), 7.09 (in, 1H), 7.17 (t, 1), 7.27 (t, M 1H), 7.60 (t, 2H), 8.18 (in, 1H), 8.26 (t, 2H ). them

Examples 94-97 5-Acetyl-2-ethyl-4-((3-fluorophenyl)amino|-6-(3-nitrophenyl)pyridazin-3(2H)-one - 4-(5-Acetyl-2-ethyl- 6-(Z-nitrophenyl)-3-oxo-2,3-dihydropyridazin-4-ilyamino)benzoic acid 5-Acetyl-4-((3Z-bromophenyl)amino|-2-ethyl-6-(Z-nitrophenyl) pyridazin-3(2H)-one 5-Acetyl-2-ethyl-4-(naphthalene-1-ylamino)-6-(3-nitrophenyl)pyridazin-3(2H)-one «

The title compounds are synthesized from 5-acetyl-2-ethyl-4-nitro-6-(3-nitrophenyl)pyridazin-3(2H)-one

Wow! Ria; 7, M ei aiY,, 9. May. Spent 1997, m. 40, r. 1417| and the corresponding aniline according to the method described in example 49. Data of EBI/M5 (mass spectroscopy with electrospray ionization) and retention time according to the data of РХВР h are given in table 10. и? 5 - POSTYAI IE li NI - in yav01v56 and-th in | lu | 86 47- mni Example 98 that) 5-Butyryl-4-(3-chlorophenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one

The title compound is prepared from the title compound of Preparative Example 33, and

Z-chloroaniline according to the method described in example 49. o Mass spectrum (I EM5): t/7 396 (M--1)" o Retention time: 10.2 min.

Example 99 ime) 5-Acetyl-4-((3-chlorophenyl)amino|-b6-phenyl-2-propylpyridazin-3(2H)-one

The title compound is obtained from 5-acetyl-4-nitro-6-phenyl-2-propylpyridazin-Z3(2H)-one |VOai Ria;, 60 M. ei aI., Yuogid Oezidp and Oizsomegu, 1996, 14, 53 -57) and 3-chloroaniline according to the method described in example 49.

Mass spectrum (I EM5): t/7 382 (Ma-1)"

Holding time: 9.8 min.

Example 100 5-Acetyl-2-butyl-4-((3-chlorophenyl)amino|-6-phenylpyridazin-3(2H)-one bB The title compound is obtained from 5-acetyl-2-butyl-4-nitro- b6-phenylpyridazin-3(2H)-one

M. ega!., Ogyd Oevidp apa Oivzsomegu, 1996, 14, 53-57) and 3-chloroaniline according to the method described in example 49.

Mass spectrum (IEM): t/7 396 (M--1)"

Holding time: 10.3 minutes.

Example 101 5-acetyl-4-(3-bromophenyl)amino|-2-butyl-6-phenylpyridazin-3(2H)-one

The title compound is prepared from 5-acetyl-2-butyl-4-nitro-b-phenylpyridazin-3(2H)-one. Ria?

M. ega!., Ogyd Oevidp apa Oizsomegu, 1996, 14, 53-57| and 3-bromoaniline according to the method described in example 49.

Mass spectrum (I EM5): t/72 441 (MA1)"

Holding time: 10.4 min. 70 Example 102 5-Acetyl-4-(M-(3,5-dichlorophenyl)-M-(3-fluorophenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one

A mixture of the compound indicated in the title of Example C (5mg, 0.12mmol), 3-fluorophenylboronic acid (33mgH, 0.24mmol), anhydrous copper acetate (182mg, 0.18mmol), triethylamine (0.034ml, 0.24mmol) and activated molecular sieves 4A (110 mg) in dry dichloromethane (2 ml) are stirred in air at room temperature 7/5 For 3 days. The resulting reaction mixture is filtered, and then the solvent is removed under reduced pressure.

The crude product is purified by express column chromatography (5iO", SNCI" - ASOEO), obtaining the title compound (216mg, yield 9995) as a solid substance. 9(SOCIv): 1.42 (t, 6H), 4, 30 (a, 2H), 6.76 (t, 4H), 7.05 (t, 1H), 7.25 (t, 2H), 7.40 (t, 5H).

Examples 103-107 5-Acetyl-4-Ibis(3-fluorophenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one 5-Acetyl-4-Ibis(3-chlorophenyl)amino|-2- ethyl-6-phenylpyridazin-3(2H)-one 5-Acetyl-2-ethyl-4-bis(3-methylsulfanylphenyl)amino|-6-phenylpyridazin-3(2H)-one 5-Acetyl-4-bis(3 -acetylphenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one 5-Acetyl-4-|bis-(3,5-dichlorophenyl)amino|-2-ethyl-6-phenyl-2H-pyridazine -3-on p

The compounds specified in the title are synthesized from the compound specified in the title of preparatory example 22 and an excess of the corresponding arylboronic acid according to the experimental method described in example 1. Data i)

ЕЗБИ/М5 (mass spectroscopy with electrospray ionization) and retention time according to РХВР data are shown in Table 11. сч » о ю 00000800 т з5 я

Example 108

Methyl ether 4-(M-(5-acetyl-2-ethyl-6-(4-methylsulfinylphenyl)-3-oxo-2,3-dihydropyridazin-4-yl)-M-(4-(methoxycarbonyl)phenyl) amino )-benzoic acid in c The compound indicated in the title is obtained from the compound indicated in the title of preparatory example 26 and .4-(methoxycarbonyl)-phenylboronic acid according to the method described in example 102. "» Mass spectrum (I EM5): t /72 588 (Ma-1)"

Holding time: 8.4 min.

Example 109 - I 5-Acetyl-2-cyclopropylmethyl-4-(3,5-difluoro-phenylamino)-6-phenyl-2H-pyridazin-3-one

The compound specified in the title is synthesized from the compound specified in the title of Preparative Example 29 and β-3,5-difluorophenylboronic acid according to the method described in Example 1. os Mass spectrum (IEM): t/7 396 (М--1)"

Holding time: 9.8 min. and Example 110

Ge 5-Acetyl-4-(3-fluoro-phenylamino)-2-methyl-6-phenyl-2H-pyridazin-3-one

The title compound is synthesized from 5-acetyl-4-amino-2-methyl-b-phenylpyridazin-3(2H)-one

M., Sisiapi, b., Siomappopi, M.R., Nei (Egosusiez, 1991, 32, 1173-91) and the corresponding 3-fluorophenylboronic acid

According to the method described in example 1.

Mass spectrum (I EM5): t/7 338 (Ma-1)"

F) Holding time: 8.5 minutes. ka Example 111 4-(5-Acetyl-2-methyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-ylamino)-benzoic acid v Mixture of 5-acetyl-4-amino-2-methyl-b6 -phenylpyridazin-3(2H)-one (Oa! Ria, M., Sisiapi, b., Siomappopi, M. R.,

Neyegosusiez, 1991, m. 32, r. 1173-9| (100mg, 0.41mmol), (4-methoxycarbonylphenyl)boronic acid (148mg, 0.82mmol), anhydrous copper acetate (112mg, O0.bimmol), triethylamine (0.1ml, 0.82mmol) and activated molecular sieves (520mg , 4A) in dry dichloromethane (4 ml) is stirred in air at room temperature for 48 hours. The resulting reaction mixture is filtered and then the solvent is removed under reduced PRESSURE. The resulting residue is purified by express column chromatography (5105, dichloromethane - ethyl acetate).

The product obtained in this way is suspended in a mixture of THF/Meon in a ratio of 2:3 (7 ml), PON is added

(5Omg, 1.2 mmol) and the resulting mixture is stirred at room temperature for 3 days. The solvent is then removed, the crude product is suspended in water, and the solution is acidified using a 2N solution of NOI.

It is then extracted with dichloromethane and the combined organic layers are washed with saturated salt solution and dried over NaCl. The solvent is removed, thereby obtaining a compound that is purified preparatively

HPLC/MS, thereby isolating the title compound.

Mass spectrum (IEM): t/7 364 (M--1)"

Holding time: 7.5 minutes.

Example 112 70 5-Acetyl-4-(3,5-dichloro-phenylamino)-2,6-diphenyl-2H-pyridazin-3-one

The title compound is obtained as a solid (yield 2190) from 5-acetyl-4-amino-2,6-diphenylpyridazin-3(2H)-one. Rial, M., Sisiapi, S., Siomappopi, M.R., Negegosusiev, 1991, 32, 1173-9| and 3,5-dichlorophenylboronic acid according to the method described in example 1.

Mass spectrum (I KM5): t/2 452 (Mt) 9DMSO-a in): 1.89 (in, ЗН), 7.15 (5, 2Н), 7.22 (in, 2Н), 7, 40 (t, 6H), 7.52 (t, 2H), 7.66 (a, 2H), 9.27 (re, 1H).

Example 113 5-Acetyl-4-(3-fluoro-phenylamino)-2,6-diphenyl-2H-pyridazin-3-one

The title compound was obtained as a solid (yield 5790) from 5-acetyl-4-amino-2,6-diphenylpyridazin-3(2H)-one. Rial, M., Sisiapi, S, Siomappopi, M.R., Negegosusiev, 1991, 32, 1173-9) and 3-fluorophenylboronic acid according to the method described in example 1.

Mass spectrum (CM): t/2 401 (Mt) 9DMSO-a in): 1.80 (in, ЗН), 6.91 (t, ЗН), 7.32 (а, 1Н), 7.36 (t, 6H), 7.53 (I, 2H), 7.67 (a, 2H), 9.22 (c, 1H).

Example 114 5-Acetyl-4-(naphthalene-1-ylamino)-2,6-diphenyl-2H-pyridazin-3-one Ha

The title compound was obtained as a solid (yield 2090) from 5-acetyl-4-amino-2,6-diphenylpyridazin-3(2H)-one. Rial, M., Sisiapi, p., Siomappopi, M.R., Negegosusiev, o 1991, m.32, p.1173-9| and 1-naphthaleneboronic acid according to the method described in example 1.

Mass spectrum (I KM5): t/2 433 (M'-1)

ZDMSO-yv): 1.23 (v, 2H), 7.26-7.56 (t, 11H), 7.73 (aa, 2H), 7.80 (aa, 2H), 7.94 (aa , yin), 8.03 (ai, c 1H), 9.25 (v, 1H).

Example 115 o 5-Acetyl-4-(3,5-difluoro-phenylamino)-2,6-diphenyl-2H-pyridazin-3-one

The title compound was obtained as a solid (yield 2690) from 5-acetyl-4-amino-2,6-diphenylpyridazin-3(2H)-one. Rial, M., Sisiapi, S, Siomappopi, M.R., Negegosusiev, - 1991, 32, 1173-9| and 3, 5-difluorophenylboronic acid according to the method described in example 1. h-

Mass spectrum (CM): t/2 419 (Mt) 9(DMSO-th in): 1.91 (in, ЗН), 6.82 (t, ЗН), 7.47 (t, 6Н), 7 .53 (Her, 2H), 7.65 (a, 2H), 9.28 (c, 1H).

Example 116 "5-Acetyl-4-(3-chloro-phenylamino)-2,6-diphenyl-2H-pyridazin-3-one

The title compound is obtained as a solid (yield 6190) from 5-acetyl-4-amino-2,6-diphenylpyridazin-3(2H)-one. Rial, M., Sisiapi, S, Siomappopi, M.R., Negegosusiev, and 1991, 32, 1173-91) and 3-chlorophenylboronic acid according to the method described in example 1. is» Mass spectrum (KM): t /2 417 (MA) 9DMSO-a in): 1.78 (in, 2H), 7.12 (I, 2H), 7.16 (in, 1H), 7.25 (І, 1H), 7, 35 (t, 6H), 7.54 (i 2H), 7.67 (y, 2H), 9.22 (c, 1H).

Example 117 - 4-(3-Chlorophenylamino)-2-ethyl-b6-phenyl-5-(1-phenylmethanoyl)pyridazin-2H-one - The compound specified in the title is synthesized from the compound specified in the title of preparatory example C5 and 3, of 5-difluorophenylboronic acid according to the method described in example 1. o Mass spectrum (I EM5): t/7 396 (M--1)" o 20 Retention time: 9.8 min.

Example 118

IR) 5-(3Z-Chlorophenyl)amino)-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carbaldehyde

The title compound is synthesized from the title compound of Preparative Example C6, and

of 3-chlorophenylboronic acid according to the method described in example 1. 59 Mass spectrum (HEM5): t/7 354 (Ma-1)7

Gee! Holding time: 9,Ochv.

Example 119 de Methyl ether of 5-((3-chlorophenyl)amino|-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid

The compound specified in the title is synthesized from the compound specified in the title of preparatory example 39 and 60 3-chlorophenylboronic acid according to the method described in example 1.

Mass spectrum (I EM5): t/7 384 (Ma-1)"

Holding time: 9 hours.

Example 120 4-(3-Chlorophenyl)amino|-2-ethyl-b-phenyl-5-(33-phenylpropanoyl)pyridazin-3(2H)-one b5 The compound indicated in the title is obtained as a solid (yield 21905) from of the compound specified in the title of Preparative Example 43 and 3-chlorophenylboronic acid according to the method described in Example 1.

9(SOSI"): 1.44 (Ii, ZN), 2.20 (I, 2H), 2.35 (2H), 4.30 (a, 2H), 6.74 (a, 2H), 7 .00-7.45 (t, 12H), 8.03 (5, 1H).

Example 121 4-(3,5-Dichlorophenyl)amino|-2-ethyl-b-phenyl-5-(3-phenylpropanoyl)pyridazin-3(2H)-one

The title compound is obtained as a solid (yield 3690) from the title compound of Preparative Example 43 and 3,5-dichlorophenylboronic acid according to the method described in Example 1. 9(SOCI3): 1.44 (, ЗН) , 2.37 (t, 4H), 4.29 (a, 2H), 6.59 (t, 2H), 6.76 (t, 2H), 6.9 (c, 2H), 7.08- 7.18 (t, ZN), 7.35-7.44 (t, ZN), 8.07 (in, 1H).

Example 122 3-Sh42-Ethyl-3-oxo-6-phenyl-5-(3-phenylpropanoyl)-2,3-dihydropyridazine-4-ilyamino)benzonitrile

The title compound is obtained as a solid (yield 56905) from the title compound of Preparative Example 43 and 3-cyanophenylboronic acid by the method described in Example 1. 9(SOCI3): 1.43 (5 ЗН), 2 .36 (t, 4H), 4.28 (a, 2H), 6.76 (t, 2H), 6.76 (t, 2H), 7.11-7.17 (t, 4H), 7, 39-7.45 (t, 8H), 8.33 (in, 1H).

Example 123 4-(2-Ethyl-3-oxo-6-phenyl-5-(3-phenylpropanoyl)-2,3-dihydropyridazine-4-ilyamino)benzoic acid

The title compound is obtained as a solid from the title compound of Preparative Example 43 by the experimental method described in Example 111.

Mass spectrum (I EM5): t/72 468 (MA1)"

Holding time: 9.5 minutes.

Example 124 4-(3-Chlorophenyl)amino|-2-ethyl-b-phenyl-5-(3-thien-3-ylpropanoyl)pyridazin-3(2H)-one

The title compound is obtained as a solid (yield 33905) from the title compound of Preparative Example 44 and 3-chlorophenylboronic acid according to the experimental procedure described in Example 1.

Mass spectrum (I EM5): t/72 464 (Ma-1)"

Holding time: 10.7 minutes.

Example 125 4-(3-Chlorophenyl)amino|-2-ethyl-b-phenyl-5-(3-pyridin-3-ylpropanoyl)pyridazin-3(2H)-one Ge

The title compound is obtained as a solid (yield 30905) from the title compound of Preparative Example 45 and 3-chlorophenylboronic acid according to the experimental method described in Example 1.

Mass spectrum (IM): t/7 459 (МА1)" by them

Holding time: 8.1 min.

Example 126 - 5-Acetyl-2-benzyl-4-(1-naphthylamino)-6-phenylpyridazin-3(2H)-one

The compound specified in the title is obtained as a solid from the compound specified in the title of Preparative Example 28 and 1-naphthylboronic acid according to the experimental method described in example "1.

Mass spectrum (I EM5): t/72 446 (MA1)" - s Retention time: 10.4 min. a Example 127 "» 4-K(5-acetyl-2-benzyl-3-oxo-6-phenyl- 2,3-Dihydropyridazin-4-yl)amino|Ibenzoic acid

The compound indicated in the title is obtained as a solid substance from the compound indicated in the title of preparatory example 28, according to the experimental method described in example 111. - Mass spectrum (IM): t/7 440 (MA1)" -1 Retention time: 8 , 1 min.

Examples 128-129 (9) 5-Acetyl-4-I(3,5-difluorophenyl)amino|-b-phenyl-2-(pyridin-4-ylmethyl)pyridazin-3(2H)-one o 50 5-Acetyl -4-((3-chlorophenyl)amino|-b-phenyl-2-(pyridin-4-ylmethyl)pyridazin-3(2H)-one

The compounds specified in the title are synthesized from the compound specified in the title of Preparatory Example 30 and the corresponding boronic acid according to the experimental method described in Example 71. Table 12. Example 130 4-K5-acetyl-3-oxo-2,6-diphenyl-2,3-dihydropyridazin-4-yl)iamino|benzoic acid

The title compound is obtained as a solid Kk! 5-acetyl-4-amino-2,6-diphenylpyridazin-3(2H)-one |ОСа! Rial, M., Sisiapi, s, Siomappopi, M.R., Negegosusiev, 1991, 32, 1173-99) according to the experimental method described in example 111. 65 Mass spectrum (I EM5): t/72 426 (MA1 )"

Holding time: 8, 7xMin.

Examples 131-133 5-Acetyl-2-(cyclopropylmethyl)-4-((2-fluorophenyl)amino)|-b-phenylpyridazin-3(2H)-one 5-Acetyl-4-((2-chlorophenyl)amino| -2-(cyclopropylmethyl)-b6-phenylpyridazin-3(2H)-one 5-Acetyl-2-(cyclopropylmethyl)-4-CH4-(hydroxymethyl)phenyl|amino)-6-phenylpyridazin-3(2H)-one

The compounds indicated in the title are synthesized from the compound indicated in the title of Preparative Example 29 and the corresponding boronic acid according to the experimental method described in Example 71. EBI/M5 data (mass spectroscopy with electrospray ionization) and retention time according to РХВР data are shown in Table 13 .

Я яв зв | from | 7786 to Example 134 3-15-Acetyl-2-(cyclopropylmethyl)-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl|iamino)benzonitrile

The title compound was prepared as a solid (yield 40905) from the title compound of Preparative Example 29 and 3-cyanophenylboronic acid by the method described in Example 1.

T.pl. 212.9-214.026. 9(DMSO-ав): 0.42-0.53 (t, 4Н), 1.33 (t, 1Н), 1.82 (в, ЗН), 4.02 (а, 2Н), 7.34 -7.46 (t, 9H), 9.17 (t, 1H).

Example 135 4-55-Acetyl-2-(cyclopropylmethyl)-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl|Iamino)benzoic acid

The title compound is obtained as a solid (yield 29905) from the compound indicated in the title of Preparative Example 29 by the method described in Example 111.

T.pl. 250.7-251.626. at

З(DMSO-ав): 0.43-0.53 (t, 4Н), 1.33 (t, 1Н), 1.85 (в, ЗН), 4.02 (а, 2Н), 7.05 (9, 2H), 7.33 (t, 2H), 7.42 (t, ЗН), 7.79 (a, 2H), 9.21 (c, 1H), 12.8 (rev, 1H) .

Example 136 Ge 30 5-Acetyl-2-isopropyl-4-(1-naphthylamino)-6-phenylpyridazin-3(2H)-one

The compound indicated in the title is obtained as a solid (yield 23905) from the compound indicated in the title of Preparative Example 47 and 1-naphthaleneboronic acid according to the method described in Example 1.

T.pl. 246.3-246.926. 9(СОСИ3): 1.31 (v, ЗН), 1.47 (а, 6Н), 5.42 (t, 1Н), 7.22 (t, 1Н), 7.35 (t, 6ЕН), 7.55 (t, 2H), 7.75 (a, he 35 1H), 7.87 (t, 1H), 8.01 (d, 1H), 8.19 (c, 1H). -

Example 137 5-Acetyl-4-Y(3,5-difluorophenyl)amino|-2-isopropyl-b6-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid (yield 54905) from the compound indicated in the title of Preparative Example 47 and 3,5-difluorophenylboronic acid by the method described in Example 1. 40 T.pl. 200.9-201.62С. t with 9(SOSI"): 1.43 (y, 6H), 1.82 (5, ЗН), 5.32 (t, 1Н), 6.56 (t, ЗН), 7.42 (t, 5H), 8.20 (in, 1H). "» Example 138 " 5-Acetyl-4-((3-fluorophenyl)amino|-2-isopropyl-b-phenylpyridazin-3(2H)-one

The compound specified in the title is obtained as a solid (yield 41905) from the compound specified in title 45 of Preparative Example 47 and 3-fluorophenylboronic acid according to the method described in example 1. - M.p., 173.1-173.5C. -and 9(SOCIz): 1.43 (0, EN), 1.76 (5, ЗН), 5.34 (t, 1Н), 6.76 (t, 1Н), 6.86 (t, 2Н ), 7.22 (t, 1H), 7.38 (t, 5H), 8.17 (8, 1H). others Example 139 oz 20 5-Acetyl-4-((3-chlorophenyl)amino|-2-isopropyl-b-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid (yield 80905) from the title compound of Preparative Example 47 and 3-chlorophenylboronic acid by the method described in Example 1.

T.pl. 191.7-192.296. 9(SOCI3): 1.43 (a, 6H), 1.75 (8, ЗН), 5.34 (t, 1H), 6.96 (t, 1H), 7.03 (t, 1H), 7.15 (t, 1H), 7.25 (t, 1H)y, 7.38 (t, 5H), 8.17 (c, 1H).

GF) Example 140

HF 5-Acetyl-4-((3,5-dichlorophenyl)amino)|-2-isopropyl-b-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid (yield 79905) from the title compound of Preparative Example 47 and 3,5-dichlorophenylboronic acid by the method described in Example 1.

T. pl. 201,1-202,3960. 9(SOSI"): 1.43 (y, 6H), 1.79 (v, ЗН), 5.35 (t, 1H), 6.93 (v, 2H), 7.13 (v, 1H) , 7.41 (t, 5H), 8.21 (in, 1H).

Example 141 4-(5-Acetyl-2-isopropyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|Ibenzoic acid v5 The title compound is obtained as a solid (yield 23905) from of the compound indicated in the title of preparative example 47, according to the method described in example 111.

T.pl. 266.6-267.526. 9(DMSO-az): 1.34 (a, b6H), 1.86 (c, 3H), 5.23 (t, 1H), 7.03 (a, 2), 7.32 (t, 2H ), 7.42 (t, ЗН), 7.79 (a, 2Н), 9.17 (c, 1Н), 12.71 (8, 1Н).

Examples 142-145 5-Acetyl-4-((2-fluorophenyl)amino|-2-isopropyl-b-phenylpyridazin-Z3(2H)-one 5-Acetyl-4-((2-chlorophenyl)amino|-2- isopropyl-b-phenylpyridazin-Z3(2H)-one 3-(5-Acetyl-2-isopropyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzonitrile 5-Acetyl-4- (C4-(hydroxymethyl)phenyl|amino)-2-isopropyl-6-phenylpyridazin-3(2H)-one

The compounds indicated in the title are synthesized from the compound indicated in the title of Preparative Example 47 and the corresponding boronic acid according to the experimental method described in Example 71. EBI/M5 data (mass spectroscopy with electrospray ionization) and retention time according to РХВР data are shown in Table 14 5 me 1611116 m | in | in

Examples 146-150 5-Acetyl-4-|(2-fluorophenyl)amino|-2-(2-hydroxyethyl)-6-phenylpyridazin-Z3(2H)-one 5-Acetyl-4-((2-chlorophenyl)amino |-2-(2-hydroxyethyl)-6-phenylpyridazin-Z3(2H)-one 3-15-Acetyl-2-(2-hydroxyethyl)-3-oxo-6-phenyl-2,3-dihydropyridazin-4- ilyamino)benzonitrile c 5-Acetyl-2-(2-hydroxyethyl)-4-Ch4-(hydroxymethyl)phenyl|amino)-6-phenylpyridazin-3(2H)-one 5-Acetyl-4-((3-chlorophenyl) amino|-2-(2-hydroxyethyl)-6-phenylpyridazine-Z3(2H)-one o

The compounds indicated in the title are synthesized from the compound indicated in the title of Preparative Example 49 and the corresponding boronic acid according to the method described in Example 1. EBI/M5 data (mass spectroscopy with electrospray ionization) and retention time according to РХВР data are given in Table 15. with 7 F yu in zv cha

Examples 151-155 « 5-Acetyl-6-(3-fluorophenyl)-4-(2-fluorophenyl)amino|-2-(2-hydroxyethyl)-pyridazin-3(2H)-one -o c 5-Acetyl- 4-((2-chlorophenyl)amino|-6-(3-fluorophenyl)-2-(2-hydroxyethyl)-pyridazin-3(2H)-one 3-15-Acetyl-6-(3-fluorophenyl)-2 -(2-hydroxyethyl)-3-oxo-2,3-dihydropyridazin-4-ylamino)benzonitrile; t 5-Acetyl-6-(3-fluorophenyl)-2-(2-hydroxyethyl)-4-Ch4-(hydroxymethyl)phenyl|amino)pyridazin-3(2H)-one 5-Acetyl-4-((Z- chlorophenyl)amino|-6-(3-fluorophenyl)-2-(2-hydroxyethyl)pyridazin-3(2H)-one

The compounds specified in the title are synthesized from the compound specified in the title of preparatory example 51 and -I the corresponding boronic acid according to the experimental method described in example 71. EBI/M5 -1 data (mass spectroscopy with electrospray ionization) and retention time according to РХВР data are given in table 16. according to entry 1 vv01vv vv (F) Examples 156-160

GI 3-15-Acetyl-6-(33-chlorophenyl)-2-(cyclopropylmethyl)-3-oxo-2,3-dihydropyridazine-4-ilyamino)benzamide 5-Acetyl-6-(3-chlorophenyl)-2- (cyclopropylmethyl)-4-CH4-(hydroxymethyl)phenyl|amino)pyridazin-3(2H)-one in 3-15-Acetyl-6-(3-chlorophenyl)-2-(cyclopropylmethyl)-3-oxo-2, 3-Dihydropyridazin-4-ilyamino)benzonitrile 5-Acetyl-6-(3-chlorophenyl)-2-(cyclopropylmethyl)-4-(2-fluorophenyl)amino|pyridazin-3(2H)-one 5-Acetyl-6- (3-chlorophenyl)-4-(3-chlorophenyl)amino|-2-(cyclopropylmethyl)pyridazin-3(2H)-one

The title compounds are synthesized from the title compound of Preparative Example 53 and the corresponding aniline according to the experimental procedure described in Example 49. The mixture is stirred at 65 room temperature overnight. EBI/M5 data (mass spectroscopy with electrospray ionization) and retention time according to РХВР data are shown in Table 17.

inv inv

Examples 161-162 3-15-Acetyl-2-(cyclopropylmethyl)-6-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-ilyamino)benzamide 5-Acetyl-2-(cyclopropylmethyl)-6 -(33-fluorophenyl)-4-C4-(hydroxymethyl)phenyl|amino)pyridazin-3(2H)-one

The title compounds are synthesized from the title compound of Preparative Example 55 and the corresponding aniline according to the experimental procedure described in Example 49. The mixture is stirred at room temperature overnight. The EBI/M5 data (mass spectroscopy with electrospray ionization) and the retention time according to the RHVR data are shown in Table 18.

Examples 163-168 in 3-15-Acetyl-6-(3-fluorophenyl)-2-isopropyl-3-oxo-2,3-dihydropyridazin-4-ylamino)benzamide 5-Acetyl-6-(3-fluorophenyl) -4-Ch4-(hydroxymethyl)phenyl|amino)-2-isopropyl. pyridazin-3(2H)-one H0) 3-15-Acetyl-6-(3-fluorophenyl)-2-isopropyl-3-oxo-2,3-dihydropyridazin-4-ylamino)benzonitrile 5-Acetyl-6-( 3-fluorophenyl)-4-(2-fluorophenyl)amino|-2-isopropylpyridazin-3(2H)-one 5-Acetyl-4-((3-chlorophenyl)amino|-6-(3-fluorophenyl)-2- isopropylpyridazin-3(2H)-one 5-Acetyl-4-((2-chlorophenyl)amino|-6-(3-fluorophenyl)-2-isopropylpyridazin-3(2H)-one

The compounds indicated in the title are synthesized from the compound indicated in the title of Preparative Example 57 and 1 kg of the corresponding aniline according to the experimental method described in Example 49. The mixture is stirred at room temperature overnight. The EBI/M5 data (mass spectroscopy with electrospray ionization) and the retention time according to the RHVR data are given in Table 19.

AND"

Examples 169-170 -1 15 3-CP5-Acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-ilyamino)benzonitrile 3-CP5-Acetyl-2- (cyclopropylmethyl)-6-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-ilyamino)benzamide -| The title compound is synthesized from the title compound of Preparative Example 59 and sl of the corresponding aniline according to the experimental procedure described in Example 49. The mixture is stirred at room temperature overnight. EBI/M5 data (mass spectroscopy with electrospray ionization) and retention time (95) 50 according to RHVR data are given in Table 20.

F)

Examples 171-175 o 3-15-Acetyl-6-(33-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydropyridazin-4-ilyamino)benzamide 5-Acetyl-6-(3-chlorophenyl)- 2-ethyl-4-C4-(hydroxymethyl)phenyl|amino)pyridazin-3(2H)-one bo 3-15-Acetyl-6-(3-chlorophenyl)-2-ethyl-3-oxo-2,3- dihydropyridazin-4-ilyamino)benzonitrile 5-Acetyl-6-(3-chlorophenyl)-2-ethyl-4-((2-fluorophenyl)amino|pyridazin-3(2H)-one 5-Acetyl-6-(3- chlorophenyl)-4-(2-chlorophenyl)amino|-2-ethylpyridazin-3(2H)-one

The compounds indicated in the title are synthesized from 5-acetyl-2-ethyl-4-nitro-6-(3-chlorophenyl)pyridazin-3(2H)-one |Oai

Ria7, M ei aY,, U. May. Spent 1997, m. 40, r. 1417| and the corresponding aniline according to the experimental method described in example 49. The mixture is stirred at room temperature overnight. EBI/M5 data

(mass spectroscopy with electrospray ionization) and the retention time according to РХВР data are given in Table 21.

Example 176 5-Acetyl-2-ethyl-6-(3-fluorophenyl)-4-H4-(hydroxymethyl)phenyl|amino)pyridazin-3(2H)-one

The title compound (5090) is prepared from the title compound of Preparative Example 32 and 4-aminophenylmethanol according to the procedure described in Example 49. The mixture is stirred at room temperature overnight and then the resulting product is purified by flash column chromatography (510 o, hexane - ethyl acetate)

T.pl. 161.0-162.1 9(SOSIv): 1.44 (I, ЗН), 1.73 (в, ЗН), 4.29 (а, 2Н), 4.67 (в, 2Н), 7, 10 (t, 5H), 7.33 (t, ЗН), 8.20 (c, 1H).

Example 177-180 3-15-Acetyl-2-ethyl-6-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazin-4-ilyamino)benzamide 3-15-Acetyl-2-ethyl-6-( 3-fluorophenyl)-3-oxo-2,3-dihydropyridazin-4-ilyamino)benzonitrile 5-Acetyl-2-ethyl-6-(3-fluorophenyl)-4-(2-fluorophenyl)amino|pyridazine-3(2H )-one 5-Acetyl-4-((2-chlorophenyl)amino|-2-ethyl-6-(3-fluorophenyl)pyridazin-3(2H)-one sc

The title compounds are synthesized from the title compound of Preparative Example 32 and the corresponding aniline according to the experimental procedure described in Example 49. The mixture is stirred at i) room temperature overnight. EBI/M5 data (electrospray ionization mass spectroscopy) and retention time according to РХВР data are given in Table 22.

Example 181 5-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-C4-(hydroxymethyl)phenyl|-amino)pyridazin-3(2H)-one

The title compound (yield 4395) was prepared from the title compound of Preparative Example 20 31 and 4-aminophenylmethanol according to the method described in Example 49. The mixture was stirred at room temperature overnight and the resulting product was purified by express column chromatography (510 5, hexane - ethyl acetate) ;" T.pl. 154.3-156.0 9(SOSI»v): 1.44 (Yi, ZN), 1.71 (v, ZN), 4.29 (a, 2H), 4.67 (v, 2H), 7.08 (t, 4H), 7.33 (t, 4H), 8.16 (v, 1H).

Example 182 - I 4-(5-Acetyl-2-ethyl-6-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl|amino)benzonitrile

The title compound (8090) is prepared from the title compound of Preparative Example 31 and - 4-aminobenzonitrile by the method described in Example 49. The mixture is stirred at room temperature overnight.

T.pl. 207.3-208.4 o 9(SOCIz): 1.44 (ZN), 1.86 (in, ZN), 4.29 (a, 2H), 7.06-7.16 (t, 4H) , 7.40 (t, 1), 7.57 (t, 1H), 7.59 with (t, 1H), 7.70 (t, 1H), 8.55 (v, 1H).

Examples 183-186 3-C5-Acetyl-2-ethyl-6-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazin-4-ilyamino)benzamide 3-15-Acetyl-2-ethyl-6-( 4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-ilyamino)benzonitrile 5-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-((2-fluorophenyl)amino|pyridazine-3( 2H)-one and F) 5-Acetyl-4-((2-chlorophenyl)amino|-2-ethyl-6-(4-fluorophenyl)pyridazin-3(2H)-one km The compounds indicated in the title are synthesized from the compound indicated in the title of Preparative Example 31, and the corresponding aniline according to the experimental procedure described in Example 49. The mixture was stirred at room temperature overnight. The EBI/M5 (Electrospray Ionization Mass Spectroscopy) data and the retention time according to the HCVR data are shown in Table 23. cv 184 377 8.7 z 1 c

Example 187 5-Acetyl-4-((3-chlorophenyl)amino|-2-ethyl-6-(1-naphthyl)pyridazin-3(2H)-one

The title compound is obtained as a solid (yield 83905) from the title compound of Preparative Example 63 and 3-chlorophenylboronic acid by the method described in Example 1.

Mass spectrum (I EM5): t/72 418 (M-1)" 70 Retention time: 10,Ochv.

Examples 188-227 5-Acetyl-4-((2,4-difluorophenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one 5-Acetyl-4-Y(3,4-dichlorophenyl)amino |-2-ethyl-b-phenylpyridazin-3(2H)-one 5-Acetyl-4-Y(3-chloro-4-fluorophenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one 5 -Acetyl-4-|(2-chloro-6-methylphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one 5-Acetyl-2-ethyl-4-|((5-fluoro-2 -methylphenyl)amino|-6-phenylpyridazin-3(2H)-one 5-Acetyl-2-ethyl-4-((2-methyl-5-nitrophenyl)amino|-6-phenylpyridazin-3(2H)-one 5 -Acetyl-4-((2,3-dimethylphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one 5-Acetyl-4-((2,6-difluorophenyl)amino|-2-ethyl -b6-phenylpyridazin-3(2H)-one 5-Acetyl-4-((2,5-dimethylphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one 5-Acetyl-4-(( 2,5-difluorophenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one 5-Acetyl-2-ethyl-4-Y(2-fluoro-5-nitrophenyl)amino|-b-phenylpyridazin- 3(2H)-one 5-Acetyl-2-ethyl-4-((3-fluoro-4-methylphenyl)amino|-6-phenylpyridazin-3(2H)-one 5-Acetyl-4-Y(3,4 -difluorophenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one 5-Acetyl-4-((2-bromophenyl)amino|-2-ethyl-b-phenylp iridazin-3(2H)-one 5-Acetyl-4-((2,3-difluorophenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one (o) 5-Acetyl-4-|( 5-chloro-2-methylphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one 5-Acetyl-4-|(2-chloro-5-methylphenyl)amino|-2-ethyl-6- phenylpyridazin-3(2H)-one 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-Dihydropyridazin-4-yl)amino|-3-methylbenzoic acid ch 20 5-Acetyl- 4-((2,4-dichlorophenyl)amino|-2-ethyl-b-phenylpyridazin-3(2H)-one 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3- dihydropyridazin-4-yl)amino|-2-chlorobenzoic acid (ze) 5-Acetyl-4-|(2-chloro-5-nitrophenyl)amino|-2-ethyl-b6-phenylpyridazin-Z3(2H)-one 5-Acetyl-2-ethyl-4-Y(7-hydroxy-1-naphthyl)amino|-b-phenylpyridazin-Z3(2H)-one 5-Acetyl-2-ethyl-4-((2-hydroxy-4 -methylphenyl)amino)|-b-phenylpyridazin-Z3(2H)-one - with 5-Acetyl-2-ethyl-4-((2-hydroxy-4-nitrophenyl)amino|-6-phenylpyridazin-3(2H) -one M 5-Acetyl-2-ethyl-4-((2-hydroxy-5-methylphenyl)amino)|-b-phenylpyridazin-Z3(2H)-one 5-Acetyl-2-ethyl-4-((2 -hydroxy-5-nitrophenyl)amino|-6-phenylpyridazin-3(2H)-one 5-Acetyl-2-ethyl-4-((2-methoxy-4 -nitrophenyl)amino|-6-phenylpyridazin-3(2H)-one 5-Acetyl-2-ethyl-6-phenyl-4-Ch4--"trifluoromethoxy)phenyl|amino)pyridazin-3(2H)-one" 20 5-Acetyl-4-Y(3-ethoxyphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one -in 5-Acetyl-2-ethyl-4-((2-methoxy-5-methylphenyl )amino)|-b-phenylpyridazin-Z3(2H)-one c 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-Dihydropyridazin-4-yl)amino|-1- naphthonitrile :z» 3-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-Dihydropyridazin-4-yl)amino|-5-nitrobenzoic acid 5-Acetyl-2-ethyl-4- ((Z-mercaptophenyl)amino|-6-phenylpyridazin-3(2H)-one 5-Acetyl-4-|(2-chloro-5-methoxyphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H) -one y y y y - -1 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-3-methoxybenzoic acid 5-Acetyl- 2-ethyl-4-1H3-(1-hydroxyethyl)phenyl|amino)-b-phenylpyridazin-3(2H)-one - and 5-Acetyl-2-ethyl-4-1H3-(hydroxymethyl)phenyl|amino)- 6-phenylpyridazin-3(2H)-one sl 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-3-hydroxybenzoic acid 5-Acetyl- 2-ethyl-4-(C4-(1-hydroxyethyl)phenyl |amino)-b-phenylpyridazin-3(2H)-one (95) 5-Acetyl-4-I(3,5-dimethoxyphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one

KZ The compounds indicated in the title are synthesized from 5-acetyl-2-ethyl-4-nitro-b6-phenylpyridazin-3(2H)-one |bai! Riaye, M. ei aiI,, U. May. Spent 1997, m.40, p.1417) and the corresponding aniline according to the method described in example 49. Data

ЕЗБИ/М5 (electrospray ionization mass spectroscopy) and retention time according to РХВР data are given in Table 24.

yuv1va1vYu m 018 o ev v yayu010vya i i v010vv i | yav 11vv cm 5 o sch zo ne vi cha

Example 228 5-Acetyl-4-((2,6-dimethylphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one -

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and 2,6-dimethylaniline according to the method described in example 49 (5 hours at room temperature, yield 5890). "

T.pl. 187.8-188.926. t0 9(SOSI"): 1.36 (in, ЗН), 1.46 (i, ЗН), 2.23 (in, 6Н), 4.30 (a, 2Н), 7.05 (t, Н ), 7.34 (t, 5H), 7.68 (v, 1H). 8 s Example 229; z» 5-Acetyl-2-ethyl-4-(C4-(2-hydroxyethyl)phenyl|amino)-b-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and 75 2-(4-aminophenyl)ethanol according to the method described in example 49 (3.5 hours at room temperature, purification by column express chromatography, yield 71965). -I T.pl. 145.8-146.626. sl 9 (SOSIz): 1.42 (B ЗН), 1.66 (в, ЗН), 2.84 (t, 2Н), 3.82 (t, 2Н), 4.30 (a, 2Н), 7.02 (a, 2H), 7.17 (a, 2H), 7.38 (t, 5H), 8.18 (c, 1H). (95) Example 230

Kz 5-Acetyl-2-ethyl-4-(4-nitrophenyl)amino)|-b-phenylpyridazin-Z3(2H)-one

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and 4-nitrophenylamine according to the method described in example 49 (69 hours at room temperature, yield 7390).

T.pl. 209.8-210.726. (F. Z(DMSO-yv): 1.34 ( ЗН), 2.04 (в, ЗН), 4.19 (ad, 2Н), 7.04 (а, 2Н), 7.39 (t, 2H), 7.44 (t, ЗН), 8.08 (a, ka 2H), 9.46 (c, 1H).

Example 231 in 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzonitrile

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one |Oa! Rial, M ei aY.,, 9. May. Spent 1997, m. 40, r. 1417| and 4-aminobenzonitrile according to the method described in example 49 (20 hours at room temperature, output);

T. pl. 204,1-204,526. 65 9(SOSI»v): 1.44 (i, ЗН), 1.87 (в, ЗН), 4.30 (а, 2Н), 7.06 (а, 2Н), 7.44 (t, 5H), 7.58 (4, 2H), 8.61 (in, 1H).

Example 232

3-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzamide

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and

C-aminobenzamide according to the method described in example 49 (1 hour at room temperature, yield 9095);

T. pl. 215,8-216,7260.

Z(DMSO-yv): 1.34 (ZN), 1.65 (v, ZN), 4.18 (4, 2H), 7.19 (y, 1H), 7.31 (t, 71H), 7.40 (t, 6H), 7.51 (c, 1H), 7.58 (4, 1H), 7.87 (c, 1H), 9.05 (c, 1H).

Example 233 5-Acetyl-2-ethyl-4-((2-(hydroxymethyl)phenyl|amino)-6-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and (2-aminophenyl)methanol according to the method described in example 49 (1.5 hours at room temperature, yield 48906).

T.pl. 152.8-153.926. 9UDMSO-ав): 1.34 (i, ЗН), 1.55 (5, ЗН), 4.17 (а, 2Н), 4.52 (а, 2Н), 5.36 (Б 1Н), 6 .93 (t, 1H), 7.11 (t, 2H), 7.28 (t, 2H), 7.39 (t, 4H), 8.70 (c, 1H).

Example 234 2-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-benzamide

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and 2-aminobenzamide according to the method described in example 49 (2 hours at room temperature, yield 61905).

T.pl. 185.5-186.8260. 5(DMSO-аv): 1.33 (Her ЗН), 1.79 (в, ЗН), 4.17 (4, 2н), 6.88 (y, 1), 7.03 (B 1Н), 7.26 (5 1), 7.35 (t, SI 2H), 7.44 (t, ЗН), 7.63 (t, 2H), 8.14 (v, 1H), 10.08 (5 , 1H). at

Example 235 2-(K5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzenesulfonamide

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and with 2-aminobenzenesulfonamide according to the method described in example 49 (96 hours at room temperature, with purification by column express chromatography, yield 3590);

T.pl. 120.0-122.726. o 5(DMSO-а6): 1.34 (, ЗН), 1.84 (5, ЗН), 4.19 (а, 2Н), 7.01 (9, 71Н), 7.20 (6 71Н) , 7.37 (t, 2H), 741 (t, k-.

AN), 7.70 (in, 2H), 7.81 (y, 1H), 8.74 (in, 1H). 325 Example 236 - 2-K5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzonitrile

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and "2-aminobenzonitrile according to the method described in example 49 (6 days at room temperature, yield 16905). - 10 square meters 169.7-170.22С. with 9DMSO-yv): 1.34 (Ii, ЗН), 1.69 (5, ЗН), 4.18 (d, 2Н), 7.30 (t, 4Н), 7.41 (t, ЗН) , 7.54 (i, tn), 7.76 (a, :z» 1H), 9.26 (v, 1H).

Example 237 5-Acetyl-4-((2,6-dichlorophenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one-1 15 The compound indicated in the title is obtained as a solid Kk! 5-acetyl -2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and -| of 2,6-dichlorophenylamine according to the method described in example 49 (6 days at 602C, yield 12905), mp 233.6-234.496.

C(DMSO-th c): 1.33 (Y, ЗН), 1.55 (c, ЗН), 4.17 (а, 2Н), 7.31 (t, ЗН), 7.41 (t, ЗН), 7.48 (t, 2Н), 9.03 (in, 1Н). o Example 238

From 5-Acetyl-2-ethyl-4-((2-nitrophenyl)amino)|-b-phenylpyridazin-Z3(2H)-one

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one |Oa! Ria7, M ei aiYi., 9. May. Spent 1997, M. 40, p. 1417)| and 5B 2-nitrophenylamine according to the method described in example 49 (4 days at 509C, purification by column express chromatography, yield 5096).

F, T.pl. 151.2-153.02С. име) 9UDMSO-ав): 1.33 (B ЗН), 1.87 (в, ЗН), 4.17 (а, 2), 7.21 (t, 2Н), 7.40 (t, 2Н) , 7.47 (t, ЗН), 7.58 (5 1Н), 8.07 (y, 1Н), 9.46 (в, 1Н). 60 Example 239 5-Acetyl-4-|(5-chloro-2-hydroxyphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and 2-amino-4-chlorophenol according to the method described in example 49 (2 hours at room temperature, yield 9196). 65 T.pl. 239.4-240.726. 9DMSO-yv): 1.31 (Yii, ZN), 1.60 (5, ZN), 4.14 (a, 2H), 6.75 (t, 1H), 7.00 (t, 2H), 7.27 (t, 2H), 7.40 (t,

ЗН), 8.50 (5, 1Н), 9.99 (in, 1Н).

Example 240 5-Acetyl-4-|(3-chloro-4-hydroxyphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and 4-amino-2-chlorophenol according to the method described in example 49 (2 hours at room temperature, yield 80965).

T.pl. 207.1-207.626. 9UDMSO-yv): 1.31 (Ii, ЗН), 1.62 (в, ЗН), 4.14 (а, 2Н), 6.83 (t, 2Н), 7.06 (t, 1Н), 7.25 (t, 2H), 7.38 (t, 70. ZN), 8.76 (8, 1H), 10.13 (v, 1H).

Example 241 3-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)iamino|benzenesulfonamide

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one |Oa! Ria7, M ei aiYi., 9. May. Spent 1997, M. 40, p. 1417)| and 75 C-aminobenzenesulfonamide according to the method described in example 49 (3 hours at room temperature, yield 8796).

T.pl. 192.0-194.296.

Z(DMSO-th c): 1.34 (i, ZN), 1.74 (8, ZN), 4.18 (ad, 2H), 7.17 (a, 1H), 7.33 (t, 4H), 7.45 (t, EN), 9.14 (in, 1H).

Example 242 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-1-naphthoic acid

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and 4-aminonaphthalene-1-carboxylic acid according to the method described in example 49 (24 hours at room temperature, yield 5496). Ge

T.pl. 258.1-260.2260. (5)

З(DMSO-yv): 1.36 (, ЗН), 1.41 (в, ЗН), 421 (а, 2Н), 7.24 (t, ЗН), 7.40 (t, ЗН), 7 .66 (t, 2H), 8.02 (a, 1H), 8.16 (a, 1H), 8.93 (a, 1H), 9.19 (c, 1H), 13.05 (B5, 1H).

Example 243 3-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-4-methoxybenzamide c

The title compound is obtained as a solid Kk! so 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Mei aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417) | and

Z-amino-4-methoxybenzamide according to the method described in example 49 (1 hour at room temperature, yield t) 66). them-

T.pl. 246.1-247.596.

Z(DMSO-yv): 1.33 (Yi, ZN), 1.53 (v, ZN), 3.80 (v, ZN), 4.17 (a, 2H), 7.04 (a, 1 ), 7.1-7.5 (t, 6H), 7.59 - (5, 1H), 7.7-7.8 (t, 2H), 8.52 (8, 1H).

Example 244 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-2-methoxybenzoic acid «

The title compound is obtained as a solid Kk! From 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Mei aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417) | and with 4-amino-2-methoxybenzoic acid according to the method described in example 49 (30 hours at room temperature,

From" output 8390).

T. pl. 210,9-211,826.

Z(DMSO-yv): 1.34 (B ZN), 1.88 (85, ZN), 3.71 (v, ZN), 4.18 (4, 2H), 6.62 (j, 1) , 6.74 (in, 1H), 7.2-7.5 -1 15 (t, 5H), 7.57 (j, 1H), 9.14 (in, 1H), 12.28 (B5, 1H).

Example 245 -i 5-Acetyl-2-ethyl-4-|(3-fluoro-4-hydroxyphenyl)amino|-6-phenylpyridazin-3(2H)-one sl The compound specified in the title is obtained in the form of a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and (95) 50 4-amino-2-fluorophenol according to the method described in example 49 (1 hour at room temperature, yield 83905). "from T. pl. 241.8-242.626.

Z(DMSO-yv): 1.32 (B ZN), 1.65 (in, ZN), 4.15 (4, 2H), 6.71 (B 1H), 6.80 (Her, 1H), 6.93 (y, 1), 7.26 (t, 2H), 7.39 (t, ЗН), 8.78 (c, 1H), 9.81 (c, 1H).

Example 246 5-Acetyl-2-ethyl-4-|(5-fluoro-2-hydroxyphenyl)amino|-6-phenylpyridazin-3(2H)-one (F) The compound specified in the title is obtained as a solid substance Kk!

GI of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Mei aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417) | and 2-amino-4-fluorophenol according to the method described in example 49 (24 hours at room temperature, yield 88965). in T.pl. 190.1-190.526.

C(DMSO-th c): 1.19 (i, ЗН), 1.49 (c, ЗН), 4.02 (а, 2Н), 6.6-6.8 (t, ЗН), 7, 0-7.4 (t, 5H), 8.36 (in, 1H), 9.56 (in, 1H).

Example 247 5-Acetyl-2-ethyl-4-|(b-hydroxy-1-naphthyl)amino|-b-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid Kk! be 5-acetyl-2-ethyl-4-nitro-b-phenylpyridazin-3(2H)-one (Oa! Riag, Mei ai,, U. Mei. Spet. 1997, m. 40, p. 1417) and 5-amino-2-naphthol according to the method described in example 49 (1.5 hours at room temperature, yield 76905).

T.pl. 235.5-236.726. 9UDMSO-yv): 1.21 (c, ЗН), 1.37 (B ЗН), 421 (а, 2Н), 6.98 (а, 1), 7.0-7.4 (t, 8Н) , 7.54 (a, tn), 7.83 (d, 1H), 8.96 (c, 1H), 9.84 (c, 1H).

Example 248 5-Acetyl-2-ethyl-4-I((3-fluoro-2-methylphenyl)amino|-6-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and

C-fluoro-2-methylaniline according to the method described in example 49 (1 hour at room temperature, yield 68905). 70 T.pl. 189.3-190.626.

ZDMSO-yv): 1.35 (B ЗН), 1.46 (5, ЗН), 2.11 (в, ЗН), 4.18 (4, 2Н), 6.89 (a, 1), 7 ,0-7.2 (t, ZH), 7.2-7.5 (t, 5H), 8.74 (in, 1H).

Example 249 5-Acetyl-2-ethyl-4-|(2-hydroxy-1-naphthyl)amino|-b-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and 1-amino-2-naphthol according to the method described in example 49 (4 hours at room temperature, yield 5290).

T. pl. 231,2-235,296.

Z(DMSO-yv): 1.15 (c, ZN), 1.37 (5 ZN), 4.21 (a, 2), 7.09 (a, 1), 7.2-7.5 ( t, 7H), 7.6-7.8 (t, ЗН), 8.54 (5, 1H), 9.95 (v, 1H).

Example 250 5-Acetyl-2-ethyl-4-|(5-hydroxy-1-naphthyl)amino|-b-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-b-phenylpyridazin-3(2H)-one (Са! Ria7, Mei ai., U. Mei. Spet., 1997, M. 40, p. 1417) and CEE

B5-amino-1-naphthol according to the method described in example 49 (24 hours at room temperature, output 2490). heh)

T.pl. 234.8-235.926.

Z(DMSO-yv): 1.18 (c, ЗН), 1.37 (ЗН), 4.21 (а, 2Н), 6.89 (й, 2Н), 7.2-7.5 (t , 8H), 8.0 (a, tn), 8.94 (85, 1H), 10.22 (c, 1H).

Example 251 with 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-3-fluorobenzoic acid so

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and about 4-amino-3-fluorobenzenecarboxylic acid according to the method described in example 49 (b days at room temperature, yield 78965).

Tpl. 238.1-240.950. t 9UDMSO-yv): 1.33 (B ZN), 1.78 (c, ZN), 4.17 (a, 2), 7.26 (B 1), 7.3-7.5 (t, 5H), 7.60 (a, tn), 7.66 (d, 1H), 9.07 (8, 1H), 13.14 (rve, 1H).

Example 252 "du 3-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-M,M-dimethylbenzamide with

The title compound is obtained as a solid Kk! with 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Mei aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417) | and :z» of 3-amino-M,M-dimethylbenzamide according to the method described in example 49 (24 hours at room temperature, yield 8090).

T.pl. 190.1-190.526. -I 75 9UDMSO-ав): 1.34 (6 ЗН), 1.72 (в, ЗН), 2.89 (в, ЗН), 2.94 (в, ЗН), 4.17 (а, 2Н ), 7.0-7.2 (t, ЗН), 7.2-7.5 (t, 6Н), 9.05 (in, 1Н). - Example 253 ml 3-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydrotridazin-4-yl)amino|-M-methylbenzamide

The title compound is obtained as a solid Kk! o 5-Acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one |Oa! Ria7, M ei aiY., 9. May. Spent 1997, M.40, r.1417| and

GE of 3-aminobenzoylmethylamide according to the method described in example 49 (24 hours at room temperature, yield 74906).

T.pl. 195.1-195.626. 9UDMSO-ав): 1.34 (B ЗН), 1.66 (в, ЗН), 2.74 (а, зн), 418 (ад, 2Н), 7.20 (а, 1н), 7.2 -7.6 (t, 8H), 8.35 (d, 1H), 9.06 (c, 1H).

F) Example 254 ko 5-Acetyl-2-ethyl-4-((4-nitro-1--aphthyl)amino|-6-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid Kk! for 9-acetyl-2-ethyl-4-nitro-b-phenylpyridazin-3(2H)-one (Са! Риа7, Мейа, 9. May. Spet. 1997, m. 40, p. 1417)| and 1-amino-4-nitronaphthalene by the method described in example 49 (2 hours in a microwave oven, yield 119605).

T.pl. 185.2-185.826. 9UDMSO-ав): 1.37 (B ЗН), 1.71 (в, ЗН), 4.22 (а, 2Н), 7.18 (t, 1Н), 7.3-7.5 (t, 5H), 7.73 (5 1H), 7.84 (B tn), 8.25 (a, 1Hn), 8.35 (a, 1H), 8.53 (49, 1H), 9.39 ( in, 1H). 65 Example 255 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-2-fluorobenzoic acid -B4-

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and 4-amino-2-fluorobenzoic acid according to the method described in example 49 (20 hours at room temperature, yield 7290).

T.pl. 235.7-236.226.

Z(DMSO-yv): 1.34 (B ZN), 1.96 (v, ZN), 4.18 (ad, 2H), 6.8-6.9 (t, 2H), 7.3- 7.5 (t, 5H), 7.71 (B 1H), 9.27 (8, 1H), 12.89 (c, 1H).

Example 256 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-3-chlorobenzoic acid

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and 4-amino-3-chlorobenzoic acid according to the method described in example 49 (15 days at room temperature, yield 3590).

T.pl. 197.5-198.296. 9DMSO-yv): 1.19 (, ЗН), 1.63 (5, ЗН), 4.03 (а, 2Н), 7.05 (а, 1), 7.2-7.4 (t, 5H), 7.61 (aa, tn), 7.76 (d, 1H), 8.69 (c, 1H).

Example 257 5-Acetyl-4-|(3-chloro-2-methylphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and

C-chloro-2-methylaniline according to the method described in example 49 (1.5 hours at room temperature, yield 93965).

T.pl. 219.7-220.596. 9(DMSO-th c): 1.35 (Y, ЗН), 1.45 (5, ЗН), 2.24 (c, ЗН), 4.18 (а, 2Н), 7.0-7, 1 (t, 2H), 7.2-7.5 (t, 6H), 8.81 (5, 1H). with

Example 258 Fr

4-(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzoic acid methyl ester

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and methyl ester of 4-aminobenzoic acid according to the method described in example 49 (24 hours at room temperature, yield 6195). co

T.pl. 177,8-179,H6.

C(DMSO-th c): 1.34 (i, ЗН), 1.86 (c, ЗН), 3.80 (c, ЗН), 7.07 (da, 2Н), 7.3-7, 5 (t, 5H), 7.80 (44, 2H), 9.24 (in, 1H). what)

Example 259 h- 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-5-chloro-2-methoxybenzoic acid

The title compound is obtained as a solid Kk! - 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417) | and 4-amino-5-chloro-2-methoxybenzoic acid according to the method described in example 49 (8 days at 502, yield 3095).

Z(DMSO-yv): 1.34 (Yi, ЗН), 1.79 (в, ЗН), 3.71 (в, ЗН), 4.18 (а, 2Н), 6.89 (в, 71Н ), 7.3-7.5 (t, 5H), 7.69 " (85, 1H), 8.72 (8, 1H), 12.6-12.8 (B5, 1H). - 70 Example 260 c 3-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-4-methylbenzamide; z» The compound specified in the title is obtained as a solid substance Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and

C-amino-4-methylbenzamide according to the method described in example 49 (2 hours at room temperature, yield 75,789p5). and T.pl. 236.1-237.926. -and 9UDMSO-jav): 1.36 (B ЗН), 1.37 (8, ЗН), 2.27 (в, ЗН), 4.19 (а, 2Н), 7.2-7.5 ( t, 7H), 7.51 (in, 1H), 7.63 sl (d, 1H), 7.82 (8, 1H), 8.69 (in, 1H).

Example 261 (95) 3-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-4-chlorobenzamide

Kz The compound indicated in the title is obtained in the form of a solid substance Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and

Z-amino-4-chlorobenzamide according to the method described in example 49 (48 hours at room temperature, yield 27905).

T.pl. 219.2-220.126. 9UDMSO-yv): 1.34 (B ЗН), 1.58 (5, ЗН), 4.18 (a, 2Н), 7.3-7.5 (t, 5Н), 7.47 (c, 1H), 7.57 (a, tn), 7.69 (F. (5, 1H), 7.71 (9, 1H), 7.97 (c, 1H), 8.83 (8, 1H) Example 262 5-Acetyl-4-|(4-chloro-1-naphthyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one The title compound is obtained as a solid. -acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. May. Spet. 1997, m. 40, p. 1417) | and 1-amino-4-chloronaphthalene according to the method described in example 49 (4 hours at room temperature, yield 80905).

T.pl. 191.0-192.326. 9UDMSO-yv): 1.29 (c, ЗН), 1.38 (5 ЗН), 4.22 (а, 2Н), 7.2-7.4 (t, 5Н), 7.29 (в, 1H), 7.58 (a, tn), 7.72 65 (t, 2H), 8.08 (a, Sh), 8.17 (j, 1H), 9.15 (c, 1H).

Example 263

5-Acetyl-2-ethyl-b-phenyl-4-((2,4,6-trifluorophenyl)amino|-pyridazin-3(2H)-one

The title compound is obtained as a solid Kk! 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. Mei. Spet. 1997, m. 40, p. 1417)| and 2,4,6-trifluoroaniline according to the method described in example 49 (19 hours at 502, yield 33905).

T.pl. 200.2-201.026.

C(DMSO-th c): 1.33 (Y, ЗН), 1.62 (c, ЗН), 4.17 (а, 2Н), 7.2-7.5 (t, 7Н), 8, 71 (8, 1H).

Example 264 5-Acetyl-2-ethyl-b-phenyl-4-((3,4,5-trifluorophenyl)amino|-pyridazin-3(2H)-one 70 The compound specified in the title is obtained as a solid Kk! 5 -acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ria7, Meyi aiYi., 9U. May. Spet. 1997, m. 40, p. 1417) | and

C,4,5-trifluoroaniline according to the method described in example 49 (16 hours at 502, yield 5690).

T.pl. 203.0-203.826.

C(DMSO-th c): 1.33 (Y, ЗН), 1.85 (c, ЗН), 4.17 (а, 2Н), 7.00 (da, 2Н), 7.3-7, 5 (t, 5H), 9.09 (in, 1H).

Example 265 3-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-4-chlorobenzoic acid

Add 8 mg (0.28 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one to a stirred solution.

M ei ai., 9U. Honey. Spet., 1997, m.40, p.1417) in ethanol (2 ml) add 3-amino-4-chlorobenzoic acid (95 mg, O0.55 mmol) in portions. The resulting mixture is kept in a microwave oven for three hours at 120 2960.

The resulting product was collected by filtration and washed with diethyl ether to give the title compound (5Omg, yield 4496).

T.pl. 254.6-255.996.

Z(DMSO-yv): 1.36 (B ЗН), 1.62 (в, ЗН), 4.17 (а, 2Н), 7.31 (t, 2Н), 7.42 (t, ЗН) , 7.59 (j, 1), 7.65 (v, 1H), 7.35 (4, 1H), 8.88 (8, 1H), 13.21 (rev, 1H). with

Example 266 Ge) 5-Acetyl-4-(4-(aminomethyl)phenyl|amino)-2-ethyl-b6-phenylpyridazin-3(2H)-one

To a stirred solution, 100 mg (0.348 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (|

Ria7, M ei ai., )U. May Spent 1997, m. 40, p. 1417)|) in ethanol (bml) add mrem/-butyl ether of (4-aminobenzyl) carbamic acid in portions (SailPo-Coagidoel, Seyi a). 9. May. Spent 1994, 37(5), 636-466) (116 mg, SC 0.52 mmol). The resulting mixture is stirred at room temperature for 1 hour. The resulting precipitate is collected by filtration and washed with diethyl ether. Then this product is dissolved in dichloromethane (tml) and trifluoroacetic acid (0.2 ml, 3.0 ml) is added dropwise. The resulting mixture is stirred at room temperature for 20 minutes. Another amount of dichloromethane is added and - the resulting solution is washed with a saturated solution of K»CO»z until pH 6 is reached. The organic layer is dried and

The solvent was removed from the solvent to give 7mg (yield 5495) of the title compound. -

T.pl. 138.9-139.326. 9(SOSIz): 1.44 (ZN), 1.68 (in, ZN), 1.99 (rev, 2H), 3.87 (rv5, 2H), 4.30 (a, 2H), 4, 17 (4, 2H), 7.03 (a, 2H), 7.25 (d, 2H), 7.34 (t, 5H), 8.21 (8, 1H). « 20 Example 267 -v 5-Acetyl-4-(C4-(2-aminoethyl)phenyl|amino)-2-ethyl-b-phenylpyridazin-3(2H)-one c The compound indicated in the title is obtained in the form of a solid substance ( 8496) Kk) :z" of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Oa! Ri7, Meii aili.,, 9U. May. Spet. 1997, m. 40, r. 1417)| and tert-butyl ether (2-(4-aminophenyl)ethyl|carbamic acid |Oappnaga!, p. ei aYi. Agspim deg RNnagpta?ie, 2000, m. 333(8), p. 267-74) according to the method, described in example 266. -1 T.pl. 71.8-72.596. 9(SOSIz): 1.44 ( ЗН), 1.67 (8, ЗН), 1.91 (рб5, 2Н), 2.75 (5 2Н), 2.97 (5 2Н), 4.29 ( a, 2H), 7.02 (sa,

Sh- 2H), 7.14 (9, 2H), 7.36 (t, 5H), 8.19 (v, 1H). c Example 268 5-Acetyl-2-ethyl-4-((3-fluorophenyl)amino|-6-(4-(methylthio)phenyl|pyridazin-3(2H)-one) and The title compound is obtained as a solid (output 1790) from the compound specified in

From the title of preparatory example 23, and 3-fluorophenylboronic acid according to the method described in example 1.

T.pl. 168.7-169.126.

Z(DMSO-th c): 1.33 (Y, ЗН), 1.80 (8, ЗН), 3.34 (c, ЗН), 4.17 (а, 2Н), 6.87 (t, ЗН), 7.26 (t, 5Н), 9.06 (in, 1Н).

Example 269 1-Ethyl-5-((3-fluorophenyl)amino|-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid

F. When stirring, ammonium formate (27 Ωg, 4.27 mmol) and 10956 palladium on carbon (55 mg) are added to a solution of the compound indicated in the title of Preparative Example 65 (0.5 g, 1.43 mmol) in 100 ml of ethanol, after which the resulting mixture is boiled under reflux for 1 hour. The catalyst was filtered through a pad of celite, then the solvent was removed under reduced pressure to give the title compound (0.42 g, yield 8496).

Mass spectrum (IEM): t/7 354 (M--1)" 9(SOSI"): 1.42 (i, ЗН), 4.35 (а, 2Н), 6.85 (t, ЗН) , 7.21-7.58 (t, 6H), 8.02 (8, 1H).

Example 270 65 5-(3-Chlorophenyl)amino)|-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid

A mixture of the compound indicated in the title of preparatory example 64 (1.57g, 6b, 1mmol), 3-chlorophenylboron -58c-

acid (1.24g, 7.9mmol), anhydrous copper acetate (1.6b6g, 9.15mmol), triethylamine (1.20ml, 8.5mmol) and activated molecular sieves (5g, 4A) in dry dichloromethane (75ml) stirred in air at room temperature overnight. The reaction mixture is filtered through a layer of ZO" and eluted with dichloromethane.

The solvent is removed under reduced pressure, then the obtained product is purified by column chromatography (5%, hexane - ethyl acetate), thereby obtaining 380 mg of the target product (yield 19965).

Mass spectrum (IEM): t/7 370 (Ma-1)"

Holding time: 8.3 min.

Example 271 70 1-ethyl-5-((3-fluorophenyl)amino|-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid methyl ester

To a stirred solution of the compound indicated in the title of example 270 (14Omg, O04Omol) in bml of dry

Anhydrous potassium carbonate (157mg, 0.400mmol) was added to DMF and the resulting mixture was stirred for some time. Finally, methyl iodide (157 mg, 1.11 mmol) was added and the mixture was stirred at room temperature for 1 hour. Then water is added until a solid is formed. This substance 7/5 was collected by filtration and washed with cold water to give the title compound (12Omg, yield 8390).

T.pl. 187.4-188.320. 9U(DMSO-a in): 1.34 (i, ЗН), 2.92 (in, ЗН), 4.17 (а, 2Н), 6.92 (t, ЗН), 7.34 (t, 6H), 9.25 (in, 1H).

Examples 272-273

5-((3-chlorophenyl)amino|-1-ethyl-6b-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid isopropyl ether

5-((3-chlorophenyl)amino|-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid ethyl ester

The title compounds are synthesized from the title compound of Example 270 and the appropriate alkylating agent according to the experimental procedure described in Example 271. The EBI/M5 data (electrospray ionization mass spectroscopy) and retention time according to РХВР data are given in the table 25. Ha shchi o sch to Example 274 i

Benzyl ether of 5-((3-chlorophenyl)amino)|-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid

The title compound (yield 2095) is obtained from the title compound of example 270 and benzyl bromide according to the experimental procedure described in example 271. c.

T.pl. 181.8-182.4260. y- 9U(SOCIz): 1.43 (, ЗН), 1.56 (з, ЗН), 4.32 (4, 2Н), 4.40 (в, 2Н), 6.80 (а, 2Н) , 7.05 (a, 1), 7.15-7.36 (t, 11), 7.92 (c, 1H).

The following examples illustrate the pharmaceutical compositions according to the present invention and the method of their preparation.

An example of obtaining a composition 1 - c Production of a tablet ts Composition of the composition: и?

The compound according to the present invention is 5.0 mg

Lactose 113,bmg -I Microcrystalline cellulose 28,AmMg

Crushed silicon dioxide 1.Bmg w- Magnesium stearate 1.Bmg o. 20 Using a mixer, 15 g of the compound according to the present invention is mixed with 340.8 g of lactose and 85.2 g of microcrystalline cellulose. The resulting mixture is subjected to pressing using rollers, thereby obtaining a flaky compacted material. The flaky compacted material is ground into a powder using a hammer mill, then the resulting powder is sieved through a 20-mesh sieve (number of holes per linear inch). 4.5 g of free-flowing silicon dioxide and 4.5 g of magnesium stearate are added to the sifted substance and then mixed. The product obtained after mixing is used to obtain tablets in a device for making tablets, equipped with a matrix/punch system with a diameter (Ф) of 7.5 mm, thus obtaining 3000 tablets, each of which has a mass of 150 mg. ko Example of obtaining a composition 2

Preparation of tablets with a coating Composition of the composition:

The compound according to the present invention is 5.0 mg

Lactose 95.2 mg

Corn starch dO vmg

Polyvinylpyrrolidone. K25 7, Bmg b5

Magnesium stearate 1, Bmg

Hydroxypropyl cellulose 2.3 mg

Polyethylene glycol 6000 О4mg

Titanium dioxide 11 mg

Purified talc O.7 mg

Using a fluidized bed granulator, 15 g of the compound of the present invention is mixed with 285.6 g of lactose and 122.4 g of corn starch. Separately, 22.5 g of polyvinylpyrrolidone is dissolved in 127.5 g of water in order to obtain a binder solution. Using a device for granulation in 70 fluidized, the binder solution is applied by spraying on the above mixture, thus obtaining granules. Add 4.5 g of magnesium stearate to the obtained granules and mix. The resulting mixture is placed in a device for tableting, equipped with a double-concave punch/matrix system with a diameter of 6b, 5mm, thus obtaining 3000 tablets, each of which has a mass of 150mg. A coating solution is prepared separately by suspending 6.9 g of hydroxypropylmethylcellulose 2910, 1.2 g of polyethylene glycol 6000, 3.3 g of titanium dioxide (5) and 2.1 g of purified talc in 72.6 g of water. 3000 tablets obtained as described above are coated using the above-mentioned coating solution to obtain film-coated tablets weighing 154.5 mg each.

An example of obtaining a composition Z

Obtaining capsules

Composition of the composition:

The compound according to the present invention is 5.0 mg lactose monohydrate 200 mg

Colloidal silicon dioxide 2 mm

Corn starch 20 mg p

Magnesium stearate Amg o

Mix 25g of the active compound, kg of lactose monohydrate, 1g of colloidal silicon dioxide, 100g of corn starch and 20g of magnesium stearate. The mixture is sieved through a sieve with the size of bOmesh cells and then placed in 5000 gelatin capsules. with

An example of obtaining a composition of 4 so

Obtaining the cream

Composition: Yuyu Cha

Compound according to the present invention 195

Zo Cetyl alcohol Zo -

Stearyl alcohol 490

Glycerin monostearate 490

Sorbitol monostearate 0.890 "

Sorbitol monostearate ROE 0.890 z

Liquid Vaseline Bo with Methylparaben 01896; » Propylparaben 0.029

Glycerin 1596

Purified water 10096

The cream of the emulsion type "oil in the driver's car is prepared from the ingredients listed above, using -And generally accepted methods.

Claims (21)

The formula of the invention is 1. The compound of formula (I) i (0 in ZEO in which KE! represents: - a hydrogen atom; - a group selected from acyl, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl or dialkylcarbamoyl; - an alkyl group, which is not necessarily substituted by one or more substituents selected from halogen atoms and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- or dialkylamino, acylamino, carbamoyl or mono- or dialkylcarbamoyl groups; - or a group of the formula -(СНо)-В2, in which n means an integer from 0 to 4, and 2? represents: - a cycloalkyl group; - an aryl group, which is optionally substituted by one or more substituents selected from halogen atoms or alkyl, hydroxy, alkoxy, alkylenedioxy, alkylthio, amino, mono- or dialkylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- or dialkylcarbamoyl, cyano, trifluoromethyl, difluoromethoxy or trifluoromethoxy; 70 - or 3-7-ene ring system, which includes from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms, the specified ring system is optionally substituted by one or more substituents selected from halogen atoms and alkyl, hydroxy groups , alkoxy, alkylenedioxy, amino, mono- or dialkylamino, nitro, cyano or trifluoromethyl; IN? is a substituent selected from BC 7 and an alkyl group that is substituted by a hydroxycarbonyl or alkoxycarbonyl group; VZ and VE? each independently represents a monocyclic or bicyclic aryl group, which is optionally substituted by one or more substituents selected from: - halogen atoms; - alkyl and alkylene groups, which are optionally substituted by one or more substituents selected from halogen atoms and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- or dialkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl or mono groups - or dialkylcarbamoyl; - phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulfinyl, amino, mono- or dialkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- or dialkylcarbamoyl, ureido, M'-alkylureido, M',M '-dialkylureido, alkylsulfamido, aminosulfonyl, mono- or c dialkylaminosulfonyl, cyano, difluoromethoxy or trifluoromethoxy; d) B" represents: - a hydrogen atom; - a hydroxy, alkoxy, amino, mono- or dialkylamino group; - an alkyl group, which is optionally substituted by one or more substituents selected from halogen atoms and c groups of hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- or dialkylamino, acylamino, hydroxycarbonyl, co- hydroxycarbonyl, carbamoyl and mono- or dialkylcarbamoyl; - or a group of the formula "CHNadp-Ae, t- in which n and 29 are as indicated above, provided that when B' is H and B, C and EE' are unsubstituted phenyl, then B' is not methyl, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, in which K' is a hydrogen atom; a linear or branched C 4-C 4 alkyl group, which is optionally substituted with halogen atoms and/or 1 or 2 substituents selected from the groups hydroxy, alkoxy, amino, monalkylamino and dialkylamino; or a group of the formula -(CH.),-B, in which n is an integer from O to 4, and po a represents an optionally substituted phenyl, cycloalkyl or 5-6-ene heterocyclic ring system, which includes at least one nitrogen atom. 3. The compound according to claim 2, in which K" represents an unsubstituted linear or branched C 1-C4 alkyl group or a group of the formula -(СНо),-К, in which n means 0 or 1, and K5 represents cyclopropyl, phenyl or pyridyl and 4. Compound according to claim 1, in which B? represents a hydrogen atom or a group selected from alkoxycarbonyl; carbamoyl; -I linear or branched C.4-C; an alkyl group, which is optionally substituted by a hydroxy group; or a group of the formula sl -(CH0)-B?, in which n means 0, and B b is a phenyl ring, which is optionally substituted by 1 or 2 substituents selected from halogen, alkyl, acyl, alkoxy, alkylthio and alkoxycarbonyl. at 7 o'clock 5. The compound according to claim 4, in which K? represents a hydrogen atom, an unsubstituted linear C4-C4 alkyl group, or a phenyl K2 ring, which is optionally substituted with 1 or 2 substituents selected from halogen, alkyl, acyl, alkoxy, alkylthio, and alkoxycarbonyl. 6. The compound according to claim 1, in which BZ is a phenyl or naphthyl group, which is optionally substituted by 1 or 2 substituents selected from halogen, hydroxy, alkoxy, cycloalkyloxy, alkylthio, cyano, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, acylamino , aminosulfonyl, carbamoyl, trifluoromethoxy, alkylenedioxy, F) alkyl and alkylene, where the specified alkyl and alkylene groups are optionally substituted by halogen atoms or a group selected from hydroxy, oxo, phenyl, amino and hydroxycarbonyl. 7. The compound according to claim 1, in which Kk 4 is a substituent selected from hydrogen; hydroxy; Alkoxy; amino; because monoalkylamino; dialkylamino; a linear or branched C4-C8 alkyl group, which is optionally substituted by a hydroxy, alkoxy, amino, monoalkylamino or dialkylamino group; or a group of the formula -(СНо)й-КЕ, in which n means 0, 1 or 2, and E? means a phenyl group. 8. The compound according to claim 7, in which B" is a substituent selected from hydrogen, methoxy, an unsubstituted linear or branched C4-C6 alkyl group and phenyl. 9, The compound according to claim 1, in which KO is a phenyl group, which optionally substituted with 1 or 2 substituents, selected from halogen, hydroxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulfinyl, nitro, cyano, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, ureido, M'-alkylureido, M',M'-dialkylureido and optionally substituted linear or branched S.-Landfill group. 10. The compound according to claim 9, in which ER is a phenyl group, which is optionally substituted with 1 or 2 substituents selected from halogen, alkoxy, cycloalkyloxy, alkylthio, alkylsulfinyl and nitro. 11. The compound according to claim 1, which is selected from the following compounds: 5-acetyl-2-ethyl-4-(3-fluorophenyl)amino|-6-phenylpyridazin-3Z(2H)-one; 5-acetyl-4-((3,5-difluorophenyl)amino|-2-ethyl-b6-phenylpyridazin-3Z(2H)-one; 70 5-acetyl-4-((3,5-dichlorophenyl)amino|- 2-ethyl-b6-phenylpyridazin-3Z(2H)-one; 5-acetyl-2-ethyl-4-((3-nitrophenyl)amino)-6-phenylpyridazin-3Z(2H)-one; 5-acetyl-2 -ethyl-4-(4-methylphenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-((2-methylphenyl)amino|-6-phenylpyridazin-3(2H )-one; 5-acetyl-2-ethyl-4-((2-methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-(1-nnaphthylamino)- 6-phenylpyridazin-3Z(2H)-one; 5-acetyl-2-ethyl-4-H4-(methylthio)phenyl|amino)-6-phenylpyridazin-3(2H)-one; 5-acetyl-4-(4 -acetylphenyl)amino|-2-ethyl-b-phenylpyridazin-3(2H)-one; 5-acetyl-4-Ch4-(dimethylamino)phenyl|amino)-2-ethyl-6-phenylpyridazin-3(2H)- one; 5-acetyl-2-ethyl-4-(2--aphthylamino)-6-phenylpyridazin-3Z(2H)-one; 5-acetyl-4-((2-chlorophenyl)amino|-2-ethyl-6 -phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-b6-phenyl-4-(13--'trifluoromethoxy)phenyl|amino)pyridazin-3(2H)-one; 5-acetyl-2- ethyl-b6-phenyl-4-((2--trifluoromethyl)phenyl|amino)pyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-( (2,5-dimethoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-((2-fluoro-3-methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one; Ha 5-acetyl-4-((2,3-dichlorophenyl)amino |-2-ethyl-b6-phenylpyridazin-3Z(2H)-one; 5-acetyl-4-((5-chloro-2-methoxyphenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one ; and9) 5-acetyl-2-ethyl-4-((5-fluoro-2-methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one; methyl ether 4-(15-acetyl-2-ethyl- 6-I4-(methylthio)phenyl|-3-oxo-2,3-dihydropyridazin-4-yl)iamino)benzoic acid; c 5-acetyl-2-ethyl-4-((3-fluorophenyl)amino|-6 -(4-(methylthio)phenyl|pyridazin-3(2H)-one; 4-(15-acetyl-2-ethyl-6-I4-(methylthio)phenyl|-3-oxo-2,3-dihydropyridazin-4 -ylamino)benzoic acid; o 5-acetyl-2-ethyl-6-14-(methylthio)phenyl|-4-(1-naphthylamino)pyridazin-3(2H)-one; o 5-butyryl-2-ethyl- 4-((3-fluorophenyl)amino|-6-(4-(methylthio)phenyl|Ipyridazin-3(2H)-one; 2-ethyl-5-(2-ethylbutanoyl)-4-(3-fluorophenyl)amino1 )|-6-(4-(methylthio)phenyl|pyridazin-3(2H)-one; - 2-ethyl-5-(2-ethylbutanoyl)-6-14-(methylthio)phenyl)|-4-(naphth -1-ylamino)pyridazin-3(2H)-one - methyl ester 4-(15-acetyl-2-ethyl-6-14-methylsul phenyl)phenyl|-3-oxo-2,3-dihydropyridazine-4-ilyamino)benzoic acid; 5-acetyl-2-ethyl-4-((3-fluorophenyl)amino|-6-(4-(methylsulfinyl)phenyl|pyridazin-3(2H)-one; « 5-acetyl-4-((3-chlorophenyl )amino|-2-ethyl-6-I(4--methylsulfinyl)phenyl|pyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-((2-methylphenyl)amino|-6-I (4-(methylsulfinyl)phenyl|pyridazin-3(2H)-one; - c 5-acetyl-2-ethyl-6-I4-(methylsulfinyl)phenyl|-4-(1-naphthylamino)pyridazin-3(2H) -one; c 5-acetyl-2-ethyl-6-14-(methylsulfinyl)phenyl/|-4-(3-nitrophenyl)amino|pyridazin-3(2H)-one; "» 5-acetyl-2-ethyl -6-(4-(methylsulfinyl)phenyl|-4-(2-methoxyphenyl)amino|pyridazin-3(2H)-one; 5-acetyl-2-ethyl-6-I(4-(methylsulfinyl)phenyl)|- 4-(3-methoxyphenyl)amino|pyridazin-3(2H)-one; 5-acetyl-6-3-(cyclopentyloxy)-4-methoxyphenyl/|-2-ethyl-4-((3-fluorophenyl)amino Pyridazin-3(2H)-one; 5-acetyl-2-methyl-4-(1-naphthylamino)-6-phenylpyridazin-3(2H)-one; 7 5-acetyl-4-((3,5-difluorophenyl)amino|-2-methyl-b -phenylpyridazin-3(2H)-one; 5-acetyl-4-((3-chlorophenyl)amino|-2-methyl-6-phenyl) iridazin-3(2H)-one; 5-acetyl-2-benzyl-4-((3,5-difluorophenyl)amino|-6-phenylpyridazin-3(2H)-one; o 5-acetyl-2-benzyl-4-((33-fluorophenyl)amino |-6-phenylpyridazin-3(2H)-one; Kz 5-acetyl-2-benzyl-4-(3-chlorophenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-( cyclopropylmethyl)-4-(1-naphthylamino)-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-(cyclopropylmethyl)-4-((3-fluorophenyl)amino)|-6-phenylpyridazin-3( 2H)-one; 5-acetyl-4-((3-chlorophenyl)amino|-2-(cyclopropylmethyl)-6-phenylpyridazin-3Z(2H)-one; 5-acetyl-4-(1-nnaphthylamino)-6 -phenyl-2-pyridin-4-ylmethylpyridazin-3(2H)-one; F, 5-acetyl-4-(3-fluorophenyl)amino|-6-phenyl-2-pyridin-4-ylmethylpyridazin-3(2H) -one; ko 5-acetyl-2-ethyl-4-((3-methylphenyl)amino|-6-phenylpyridazin-3(2H)-one; 4-K5-acetyl-2-ethyl-3-oxo-6- phenyl-2,3-dihydropyridazin-4-yl)amino|Ibenzoic acid; in 2-K5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|Ibenzoic acid 5-acetyl-4-((3-chlorophenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one; 5-acetyl-4-(3-bromophenyl)amino|-2-ethyl-b6 -phenylpyridazin-3(2H)-one; 5-acetyl-4-((3,4-di methoxyphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-C4-(hydroxymethyl)phenyl|amino)-6-phenylpyridazin-3(2H)-one; 65 5-acetyl-4-(1,1-biphenyl-4-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-b-phenyl-4-(5,6,7 8-tetrahydronaphthalene-1-ylamino)pyridazin-3(2H)-one; 5-acetyl-4-II3-(cyclopentyloxy)-4-methoxyphenyl|amino)-2-ethyl-b6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-N-methyl-N-phenylamino|-b-phenylpyridazin-3Z(2H)-one; 5-acetyl-4-(1,3-benzodioxol-5-ylamino)-2-ethyl-b-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-((4-methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-4-(4-chlorophenyl)amino|-2-ethyl-6- phenylpyridazin-3(2H)-one; 5-acetyl-4-(4-bromophenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-b6-phenyl- 4-4I3--trifluoromethyl)phenyl|amino)pyridazin-3(2H)-one; 5-acetyl-4-((3-chloro-4-methoxyphenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one; 70 5-acetyl-2-ethyl-4-((3-hydroxyphenyl )amino|-6-phenylpyridazin-3(2H)-one; 3-(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzoic acid; 5 -acetyl-2-ethyl-4-((2-fluorophenyl)amino|-6-phenylpyridazin-3Z(2H)-one; ethyl ether 4-(5-acetyl-2-ethyl-3-oxo-6-phenyl- 2,3-dihydropyridazin-4-ylamino)benzoic acid; 5-acetyl-2-ethyl-4-(4-fluorophenyl)amino|-6-phenylpyridazin-3Z(2H)-one; 2-K5-acetyl-2- ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-4-fluorobenzoic acid; 3-(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3 -dihydropyridazin-4-yl)amino|benzonitrile; 4-K5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino)|-2-hydroxybenzoic acid; 5-acetyl-2-ethyl-4-((3-hydroxy-4-methoxyphenyl)amino|-b6-phenylpyridazin-3Z(2H)-one; 4-K5-acetyl-2-ethyl-3-oxo-6- phenyl-2,3-dihydropyridazin-4-yl)amino|Senzamide; 5-acetyl-2-ethyl-4-(13-(methylthio)phenyl|amino)-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-((3-methoxyphenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-4-(3-acetylphenyl)amino|-2-ethyl-b- phenylpyridazin-3(2H)-one; TA-K5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|phenylacetic acid; 5-acetyl-4-I(I4-(tert-butylphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one; 4-K5-acetyl-2-ethyl-3-oxo-6- phenyl-2,3-dihydropyridazin-4-yl)amino|benzenesulfonamide; 4-(A-((5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|phenyl)-4-oxobutanoic acid; i) 3-(5- acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|-N-butylbenzenesulfonamide; 5-acetyl-2-ethyl-4-(1-oxo-2,3-dihydro-1H-inden-5-yl)amino|-6-phenylpyridazin-3(2H)-one; M-14-(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|phenyl)acetamide; c zo 4-(b-acetyl-6-(3-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydropyridazin-4-ylamino|Ibenzoic acid; 5-acetyl-6-(3-chlorophenyl)- 4-(3-chlorophenyl)amino|-2-ethylpyridazin-3(2H)-one; o 5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-((33-fluorophenyl)amino|pyridazin- 3(2H)-one; 5-acetyl-4-(3-chlorophenyl)amino|-2-ethyl-6-(4-fluorophenyl)pyridazin-3(2H)-one; 5-acetyl-4-(3 -bromophenyl)amino|-2-ethyl-6-(3Z-fluorophenyl)pyridazin-3(2H)-one; 3-fluorophenyl)pyridazin-3(2H)-one; 5-acetyl-4-(3-chlorophenyl)amino|-2-ethyl-6-(3-fluorophenyl)pyridazin-3(2H)-one; 5 -acetyl-4-(3-chlorophenyl)amino|-2-ethyl-6-(3-nitrophenyl)pyridazin-3Z(2H)-one; 5-acetyl-2-ethyl-4-((3-fluorophenyl)amino |-6-(3-nitrophenyl)pyridazin-3Z(2H)-one; 4-(5-acetyl-2-ethyl-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazin-4-yl |Iamino)benzoic acid; « 5-acetyl-4-(3-bromophenyl)amino|-2-ethyl-6-(3-nitrophenyl)pyridazin-3(2H)-one; with c 5-acetyl-2-ethyl -4-(naphthalene-1-ylamino)-6-(3-nitrophenyl)pyridazin-3(2H)-one; . 5-butyryl-4-((3-chlorophenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one; 5-acetyl-4-(3-chlorophenyl)amino|-6-phenyl -2-propylpyridazin-3(2H)-one; 5-acetyl-2-butyl-4-((3-chlorophenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-4-(Z -bromophenyl)amino|-2-butyl-6-phenylpyridazin-3(2H)-one;-I 5-acetyl-4-(M-(3,5-dichlorophenyl)-M-(3-fluorophenyl)amino|- 2-ethyl-b6-phenylpyridazin-3(2H)-one; 5-acetyl-4-bis(3-fluorophenyl)amino|-2-ethyl-b6-phenylpyridazin-3(2H)-one; 5-acetyl -4-Ibis(3-chlorophenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one; c 5-acetyl-2-ethyl-4-Ibis(3-methylsulfanylphenyl)amino|-6-phenylpyridazine -3(2H)-one; 5-acetyl-4-Ibis(3-acetylphenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one; o 5-acetyl-4-|bis-(3 ,5-dichlorophenyl)amino|-2-ethyl-6-phenyl-2H-pyridazin-3-one; 4-(M-(5-acetyl-2-ethyl-6-(4-methylsulfinylphenyl)-3) methyl ester -oxo-2,3-dihydropyridazin-4-yl)-M-(4-(methoxycarbonyl)phenyl amino)benzoic acid; 5-acetyl-2-(cyclopropylmethyl)-4-((3,5-difluorophenyl)amino| -6-phenylpyridazin-3(2H)-one; 5-acetyl-4-(3-fluorophenyl)amine o|-2-methyl-b6-phenylpyridazin-3(2H)-one; F) 4-K5-acetyl-2-methyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzoic acid; ka 5-acetyl-4-((3,5-dichlorophenyl)amino|-2,6-diphenylpyridazin-3Z(2H)-one; 5-acetyl-4-((3-fluorophenyl)amino|-2,6- diphenylpyridazin-3Z(2H)-one; in 5-acetyl-4-(1-naphthylamino)-2,6-diphenylpyridazin-3Z(2H)-one; 5-acetyl-4-((3,5-difluorophenyl)amino |-2,6-diphenylpyridazin-3Z(2H)-one; 5-acetyl-4-(3-chlorophenyl)amino|-2,6-diphenylpyridazin-3Z(2H)-one; 5-benzoyl-4-(Z -chlorophenyl)amino|-2-ethyl-b6-methylpyridazin-3(2H)-one; 5-(3-chlorophenyl)amino)|-1-ethyl-6b-oxo-3-phenyl-1,6-dihydropyridazin- 4-carbaldehyde; 65 methyl ester of 5-(3-chlorophenyl)amino)|-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid; 5-acetyl-4-((Z -chlorophenyl)amino|-2-(2-hydroxyethyl)-6-phenylpyridazin-3Z(2H)-one; 5-acetyl-4-((3-chlorophenyl)amino|-2-(2--dimethylamino)ethyl|-b-phenylpyridazin-3(2H)-one; 5-acetyl-2-cyclobutyl-4-((3 ,5-dichlorophenyl)amino)|-b-phenylpyridazin-3(2H)-one; 5-acetyl-4-(3-chlorophenyl)(2-hydroxyethyl)amino|-2-ethyl-b6-phenylpyridazin-3Z(2H )-one; M-(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)-M-(3-chlorophenyl)urea; 4-(3-chlorophenyl) amino|-5-(dimethylamino)acetyl|-2-ethyl-b6-phenylpyridazin-3(2H)-one; 4-(2-ethyl-5-(methoxyacetyl)-6-phenyl-3-oxo-2,3 -dihydropyridazine-4-ylidamino)benzoic acid, 5-(3-cyanophenyl)amino)-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxamide; 5-(3-cyanophenyl)amino)-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid; 70 3-4-acetyl-5-((3,5-difluorophenyl)amino)|-1-ethyl-6-oxo-1,6-dihydropyridazin-33-yl)/benzoic acid; 3-4-acetyl-5-((3,5-difluorophenyl)amino)|-1-ethyl-6-oxo-1,6-dihydropyridazin-3-ylbenzonitrile; IM-(3--4-acetyl-5-((3,5-difluorophenyl)amino|-1-ethyl-6b-oxo-1,6-dihydropyridazin-3-iluphenyl)urea; 5-acetyl-4-( (3-Chlorophenyl)amino|-6-phenylpyridazin-3(2H)-one. 12. The compound according to claim 11, which is one of the following compounds: 5-acetyl-2-ethyl-4-((3-fluorophenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-4- ((3,5-difluorophenyl)amino|-2-ethyl-b-phenylpyridazin-3(2H)-one; 5-acetyl-2-ethyl-4-(1-naphthylamino)-6-phenylpyridazin-3(2H) -one; 5-acetyl-4-((2-chlorophenyl)amino|-2-ethyl-6-phenylpyridazin-3(2H)-one; 4-((5-acetyl-2-ethyl-6-I4-( methylthio)phenyl|-3-oxo-2,3-dihydropyridazin-4-yl)amino)benzoic acid; 5-acetyl-2-ethyl-4-((2-methylphenyl)amino)|-6-(4-( methylsulfinyl)phenyl|pyridazin-3(2H)-one; 5-acetyl-6-3-(cyclopentyloxy)-4-methoxyphenyl|-2-ethyl-4-((3-fluorophenyl)amino|pyridazin-3(2H )-one; 5-acetyl-4-((3,5-difluorophenyl)amino|-2-methyl-6-phenylpyridazin-3(2H)-one; 5-acetyl-2-(cyclopropylmethyl)-4-(( 3-fluorophenyl)amino|-6-phenylpyridazin-3(2H)-one; 5-acetyl-4-((3-chlorophenyl)amino|-2-(cyclopropylmethyl)-6-phenylpyridazin-3(2H)-one; 4-(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzoic acid; 5-acetyl-4-((3-chlorophenyl)amino|- 2-ethyl-6-phenylpyridazin-3(2H)-one; i) 3-K5 -acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino|benzonitrile; 4-(5-acetyl-6-(3-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydropyridazin-4-ylamino|benzoic acid; 5-acetyl-6-(3-chlorophenyl)-2- ethyl-4-((3-fluorophenyl)amino|pyridazin-3(2H)-one; c zo 5-acetyl-2-ethyl-4-((3-fluorophenyl)amino|-6-(3-fluorophenyl)pyridazine -3(2H)-one; 5-acetyl-4-((3-chlorophenyl)amino|-2-ethyl-6-(3-fluorophenyl)pyridazin-3(2H)-one; and, 5-acetyl-2 -ethyl-4-(naphthalene-1-ylamino)-6-(3-nitrophenyl)pyridazin-3(2H)-one; 5-acetyl-2-(cyclopropylmethyl)-4-((3,5-difluorophenyl) amino|-b-phenylpyridazin-3(2H)-one. 13. The method of obtaining the compound of formula (I) according to any of the previous clauses, where K2 means H, which includes - the interaction of the corresponding derivative 4-aminopyridazin-Z(2H)-one (II) - and "(I with all the wells where B", B and 2? are as specified in any of claims 1-3 and 7-10, and the corresponding boronic acid (Pa) 415 BZ-B(OH)", (Ша) -I in which EZ is as set forth in claims 1 to 6. -1 14. The method of obtaining the compound of formula (I) according to any of claims 1-12, where VE? is an aryl or substituted aryl that involves the interaction of the corresponding derivative 4-aminopyridazin-3(2H)-one (IM) with Uk A CM with ВЩ 5 ШНШ (Ф) where B", BZ, B and BZ are as indicated in any of claims 1-3 and claims 6-10, and the corresponding boronic acid (PID) their) B2-B(OH)", (ШВ) where B? represents an aryl or substituted aryl group. 60 15. The method of obtaining the compound of formula (I) according to any of claims 1-12, which includes the interaction of the corresponding derivative 4-nitropyridazin-3Z(2H)-one (M) b5 B: what PAK I eat Not MELONS. 70 where B", B and 2? are as specified in any of claims 1-3 and claims 7-10, and the corresponding amine (MI) Kz- and where B2 and BZ are as specified in any of which of claim 1 and claims 4-6. 16. The compound according to any one of claims 1-12, intended for the treatment of a disease state or disease that is amenable to treatment by inhibition of phosphodiesterase 4. 17. A pharmaceutical composition comprising a compound according to any one of claims 1-12 in admixture with a pharmaceutically acceptable carrier or diluent. 18. Use of a compound according to any one of claims 1-12 for the manufacture of a medicinal product for the treatment of a disease state or disease amenable to treatment by inhibiting phosphodiesterase 4. 19. Use according to claim 18, according to which the disease state is asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis, or irritable bowel syndrome. 20. A method of treating a patient who is susceptible to a medically treatable condition or disease by inhibiting phosphodiesterase 4, the method involves administering to said patient an effective amount of the compound according to any of claims 1-12. and) 21. The method according to claim 20, according to which the disease state is asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis or increased intestinal irritability. with i | | | Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2006, M 12, 15.12.2006. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. in and - - and? -i -i 1 (95) Ko) ime) 60 b5